# ent

id: cord-000125-uvf5qzfd
type: DISEASE
entity:
  human immunodeEciency virus HIV based lentiviral vector 32 37 and sh PCAF was constructed on the basis of a previously reported sequence 38 Plasmid sh B971 H1


id: cord-254492-42d77vxf
type: PROTEIN
entity:
  tumor necrosis factor receptor family member latent membrane protein 1 A protein kinase IFN inducible doublestranded RNA


id: cord-261532-q923xxn2
type: PROTEIN
entity:
  adaptor molecule 1 TIR Toll interleukin 1 receptor Th2 T helper type 2 TNF tumor necrosis factor TRAM TRIF


id: cord-261532-q923xxn2
type: GGP
entity:
  HSV herpes simplex virus type IFIX IFN inducible protein X Ig immunoglobulin IRAK IL 1R associated kinase IRF interferon regulatory factors IPS 1 interferon promoter stimulator 1 ISG IFN


id: cord-261532-q923xxn2
type: CHEBI
entity:
  adaptor molecule 1 TIR Toll interleukin 1 receptor Th2 T helper type 2 TNF tumor necrosis factor TRAM TRIF related adaptor molecule


id: cord-252485-cxi3cr15
type: GGP
entity:
  IFN β and SG like structures Figure 3 Supplementary Figure S3 In all cases G3BP1 positive granular structures


id: cord-001129-gi2kswai
type: DNA
entity:
  Figure S2 Mammalian MDA5 nucleotide coding region sequences alignment MDA5 nucleotide coding region sequences


id: cord-299964-sn5o3ugb
type: WORK_OF_ART
entity:
  The Ubiquitin proteasome System Is Necessary for the Efficient Replication of Human Astrovirus Deubiquitinating


id: cord-254549-ev0oesu0
type: GGP
entity:
  Parkinson s disease record linkage studies A loss of function variant of the antiviral molecule MAVS


id: cord-268438-bjs5oliw
type: PROTEIN
entity:
  amino acids 1 187 zbRIG I 2CARD 188 937 zbRIG I 2CARD 812 927 zbRIG I RD and 188 811 zbRIG I 2CARD RD


id: cord-305737-bnzd7b25
type: DNA
entity:
  viral genome 51 Hantaan virus Crimean Congo haemorrhagic fever virus and Borna disease virus posttranscriptionally process the 5 0 end


id: cord-311823-85wj08gr
type: DISEASE
entity:
  influenza A virus infected lung epithelial cells the role of the nonstructural NS1 protein in the evasion of the host innate defense


id: cord-257052-cik2wmlk
type: GGP
entity:
  ISG15 reverse 5 AGGCCGTACTCCCCCAG 3 β actin forward 5 TGGAATCCTGTGGCATCCATGAAAC 3 β actin reverse 5 TAAAACGCAGCTCAGTAACAGTCCG 3 HEK293T cells


id: cord-257052-cik2wmlk
type: ORG
entity:
  The Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Inhibits Type I Interferon Production


id: cord-284156-btb4oodz
type: GGP
entity:
  Kaposi s sarcoma associated herpesvirusencoded deubiquitinase ORF64 Regulation of RIG I like receptor


id: cord-306533-lvm11o4r
type: GGP
entity:
  RIG I stimulator of interferon genes STING tumor necrosis factor receptor associated factors TRAFs interferon regulatory factor


id: cord-299754-tgexahwd
type: PROTEIN
entity:
  tumor necrosis factor TNF receptor associated factors TRAFs 3 and 6 80 81 Downstream of TRAF6 the UBD containing adaptor TGF β activated kinase 1 TAK1 Mitogen


id: cord-299754-tgexahwd
type: PROTEIN
entity:
  activated kinase 1 TAK1 MAP3K7 binding protein TAB 2 Myeloid differentiation primary response gene 88 MyD88 TIR domain


id: cord-299754-tgexahwd
type: PROTEIN
entity:
  tumor necrosis factor TNF receptor associated factors TRAF family memberassociated NF κB activator TANK


id: cord-312075-asbt0mcj
type: DNA
entity:
  2016 11 11 journal Front Immunol DOI 10 3389 fimmu 2016 00498 sha add093424f4f1c1da746abb3227193fb2fefbefa doc_id 312075 cord_uid asbt0mcj


id: cord-313957-hviv5zar
type: DNA
entity:
  ISG15 interferon stimulated gene 15 UFM1 ubiquitin fold modifier 1 URM1 ubiquitin related modifier 1


id: cord-313957-hviv5zar
type: ORG
entity:
  Involvement of the N Terminal Deubiquitinating Protease Domain of Human Cytomegalovirus UL48 Tegument Protein in Autoubiquitination Virion Stability and Virus Entry High


id: cord-131093-osukknqr
type: DNA
entity:
  LSC 9 10 3 2 farmer 8 7 10 2 52 payment 9 9 10 3 3 market 8 6 10 2 53 agribusi 9 8 10 3 4 farm 8 3 10 2 54 economi 9 6 10 3 5 price 8 1 10 2 55 wtp 9 6 10 3 6 food 7 2 10 2 56 method 9 4 10 3 7 polici 6 10 2 57 choic 9 3 10 3 8 product 4 8 10 2 58 competit 9 3 10 3 9 econom 3 6 10 2 59 domest 9 1 10 3 10 household 3 5 10 2 60 conclus 8 8 10 3 11 consum 3 3 10 2 61 clinic 8 8 10 3 12 incom 3 3 10 2 62 nutrit 8 6 10 3 13 countri 3 2 10 2 63 veget 8 6 10 3 14 sector 3 1 3 10 2 76 polyphenol 6 9 10 3 27 feed 1 2 10 2 77 genotyp 6 9 10 3 28 rice 1 2 10 2 78 grown 6 9 10 3 29 season 1 2 10 2 79 greenhous 6 8 10 3 30 irrig 1 2 10 2 80 anim 6 8 10 3 31 veget 1 2 10 2 81 intak 6 7 10 3 32 nitrogen 1 2 10 2 82 studi 6 7 10 3 33 livestock 1 1 10 2 83 ferment 6 6 10 3 34 phenol 1 1 10 2 84 corn 6 4 10 3 35 growth 1 1 10 2 85 meat 6 4 10 3 36 harvest 1 10 2 86 grow 6 4 10 3 37 concentr 1 10 2 87 fresh 6 4 10 3 38 milk 1 10 2 88 pakistan 6 3 10 3 39 grass 9 9 10 3 89 plot 6 3 10 3 40 weight 9 9 10 3 90 dietari 6 2 10 3 41 grain 9 9 10 3 91 per 6 2 10 3 42 antioxid 9 8 10 3 92 anthocyanin 6 1 10 3 43 nutrit 9 7 10 3 93 bean 6 1 10 3 44 dairi 9 6 10 3 94 tillag 6 10 3 45 soybean 9 5 10 3 95 rumin 6 10 3 46 graze 9 5 10 3 96 winter 5 9 10 3 47 biomass 9 3 10 3 97 potato 5 8 10 3 48 cattl 9 2 10 3 98 rumen 5 8 10 3 49 manur 9 1 10 3 99 compound 5 8 10 3 50 trait 8 5 10 3 100 grassland 5 8 10 3 2 2 10 2 83 tillag 1 10 2 34 growth 2 10 2 84 differ 9 9 10 3 35 genet 1 9 10 2 85 manag 9 9 10 3 36 shoot 1 9 10 2 86 three 9 7 10 3 37 patient 1 9 10 2 87 four 9 7 10 3 38 field 1 8 10 2 88 manur 9 6 10 3 39 qtl 1 8 10 2 89 grower 9 6 10 3 40 veget 1 8 10 2 90 qualiti 9 5 10 3 41 grow 1 8 10 2 91 tomato 9 4 10 3 42 nutrient 1 8 10 2 92 barley 9 4 10 3 43 speci 1 8 10 2 93 chromosom 9 2 10 3 44 triticum 1 7 10 2 94 method 9 1 10 3 45 leav 1 7 10 2 95 popul 9 10 3 46 water 1 7 10 2 96 treatment 8 9 10 3 47 inocul 1 5 10 2 97 spring 8 9 10 3 48 paper 1 5 10 2 98 suscept 8 8 10 3 49 nitrogen 1 5 10 2 99 fresh 8 7 10 3 50 orchard 1 5 10 2 100 progeni 8 7 10 3 2 2 10 2 87 cavernosum 1 10 2 38 spermatogen 2 10 2 88 glutathion 1 10 2 39 intracytoplasm 1 9 10 2 89 superoxid 9 8 10 3 40 normal 1 9 10 2 90 assay 9 8 10 3 41 divid 1 9 10 2 91 express 9 7 10 3 42 level 1 9 10 2 92 oestradiol 9 7 10 3 43 iief 1 8 10 2 93 fragment 9 6 10 3 44 asthenozoosperm 1 7 10 2 94 albuginea 9 6 10 3 45 decreas 1 7 10 2 95 simul 9 5 10 3 46 normozoosperm 1 7 10 2 96 stimul 9 5 10 3 47 cauda 1 6 10 2 97 ielt 9 5 10 3 48 leydig 1 6 10 2 98 lutein 9 5 10 3 49 serum 1 6 10 2 99 method 9 5 10 3 50 icsi 1 6 10 2 100 peroxid 9 5 10 3 anthropolog 4 7 10 2 52 radiocarbon 9 8 10 3 3 ethnograph 4 5 10 2 53 stone 9 8 10 3 4 social 4 3 10 2 54 live 9 7 10 3 5 polit 3 1 10 2 55 chronolog 9 6 10 3 6 cultur 3 1 10 2 56 individu 9 5 10 3 7 argu 2 7 10 2 57 world 9 1 10 3 8 articl 2 4 10 2 58 earli 9 1 10 3 9 peopl 2 3 10 2 59 debat 9 10 3 10 centuri 2 1 10 2 60 effect 9 10 3 11 histor 2 1 10 2 61 interpret 9 10 3 12 neolith 2 10 2 62 pleistocen 9 10 3 13 site 2 10 2 63 understand 8 7 10 3 14 excav 1 9 10 2 64 middl 8 7 10 3 15 societi 1 9 10 2 65 moral 8 6 10 3 16 fieldwork 1 1 9 10 2 81 mesolith 1 10 2 32 southern 1 9 10 2 82 place 1 10 2 33 interpret 1 9 10 2 83 polit 1 10 2 34 evid 1 8 10 2 84 iron 1 10 2 35 cal 1 8 10 2 85 town 1 10 2 36 tomb 1 8 10 2 86 decor 1 10 2 37 effect 1 8 10 2 87 record 1 10 2 38 context 1 7 10 2 88 conclus 9 8 10 3 39 remain 1 6 10 2 89 taphonom 9 8 10 3 40 mediev 1 6 10 2 90 prehistori 9 7 10 3 41 artifact 1 6 10 2 91 east 9 7 10 3 42 middl 1 6 10 2 92 europ 9 7 10 3 43 occup 1 6 10 2 93 reduc 9 7 10 3 44 patient 1 5 10 2 94 isotop 9 6 10 3 45 hunter 1 5 10 2 95 histori 9 5 10 3 46 northern 1 5 10 2 96 templ 9 5 10 3 47 zooarchaeolog 1 5 10 2 97 citi 9 5 10 3 48 social 1 5 10 2 98 earliest 9 4 10 3 49 cemeteri 1 4 10 2 99 bone 9 4 10 3 50 north 1 4 10 2 100 central 9 4 10 3 1 3 10 2 82 sampl 6 9 10 3 33 cell 1 2 10 2 83 histori 6 9 10 3 34 tradit 1 2 10 2 84 detect 6 8 10 3 35 typolog 1 2 10 2 85 decreas 6 7 10 3 36 sustain 1 1 10 2 86 idea 6 7 10 3 37 twentieth 1 10 2 87 new 6 7 10 3 38 conserv 9 7 10 3 88 nineteenth 6 6 10 3 39 earthen 9 6 10 3 89 technolog 6 6 10 3 40 digit 9 6 10 3 90 induc 6 6 10 3 41 preserv 9 5 10 3 91 creation 6 6 10 3 42 conclus 9 4 10 3 92 acid 6 6 10 3 43 show 9 3 10 3 93 higher 6 5 10 3 44 residenti 9 2 10 3 94 survey 6 5 10 3 45 villag 9 1 10 3 95 dwell 6 4 10 3 46 environ 9 10 3 96 way 6 3 10 3 47 today 8 9 10 3 97 social 6 3 10 3 48 clinic 8 8 10 3 98 obtain 6 3 10 3 49 artist 8 7 10 3 99 high 6 1 10 3 50 materi 8 7 10 3 100 gene 6 1 10 3 1 2 10 2 87 beauti 6 9 10 3 38 decor 1 2 10 2 88 protein 6 9 10 3 39 increas 1 2 10 2 89 higher 6 9 10 3 40 project 1 2 10 2 90 low 6 9 10 3 41 depict 1 2 10 2 91 michelangelo 6 8 10 3 42 explor 1 2 10 2 92 mediev 6 7 10 3 43 high 1 1 10 2 93 christ 6 7 10 3 44 method 1 1 10 2 94 notion 6 6 10 3 45 twentieth 1 1 10 2 95 improv 6 6 10 3 46 narrat 1 1 10 2 96 induc 6 6 10 3 47 social 1 1 10 2 97 ratio 6 5 10 3 48 effect 1 10 2 98 style 6 5 10 3 49 conclus 1 10 2 99 roman 6 5 10 3 50 music 1 10 2 100 diseas 6 3 10 3 telescop 9 9 10 2 53 gev 1 8 10 2 4 stellar 9 8 10 2 54 baryon 1 8 10 2 5 galact 6 6 10 2 55 spectra 1 8 10 2 6 mass 5 9 10 2 56 near 1 7 10 2 7 cosmolog 5 4 10 2 57 relativist 1 6 10 2 8 luminos 5 1 10 2 58 space 1 6 10 2 9 redshift 5 10 2 59 astronom 1 6 10 2 10 observ 4 9 10 2 60 model 1 6 10 2 11 cosmic 4 5 10 2 61 giant 1 6 10 2 12 gravit 4 5 10 2 62 larg 1 6 10 2 13 accret 3 9 10 2 63 angular 1 6 10 2 14 observatori 3 7 10 2 64 dot 1 6 10 2 15 circl 3 6 10 2 65 agn 1 propos 7 10 2 52 examin 1 10 2 3 system 5 7 10 2 53 trajectori 9 9 10 3 4 control 4 4 10 2 54 year 9 9 10 3 5 robot 3 9 10 2 55 constraint 9 5 10 3 6 problem 3 8 10 2 56 background 9 4 10 3 7 algorithm 3 7 10 2 57 converg 9 3 10 3 8 simul 3 6 10 2 58 motion 9 2 10 3 9 lyapunov 2 6 10 2 59 acid 9 2 10 3 10 nonlinear 2 6 10 2 60 inequ 9 1 10 3 11 design 2 4 10 2 61 assess 9 1 10 3 12 conclus 2 3 10 2 62 network 9 10 3 13 studi 2 1 9 10 2 81 nest 1 10 2 32 season 1 8 10 2 82 prey 1 10 2 33 patient 1 8 10 2 83 woodland 9 9 10 3 34 endem 1 8 10 2 84 mammal 9 9 10 3 35 north 1 8 10 2 85 clinic 9 9 10 3 36 extinct 1 8 10 2 86 suggest 9 9 10 3 37 assemblag 1 8 10 2 87 america 9 8 10 3 38 plant 1 7 10 2 88 invertebr 9 8 10 3 39 spatial 1 7 10 2 89 within 9 8 10 3 40 anthropogen 1 7 10 2 90 disturb 9 7 10 3 41 predat 1 7 10 2 91 cell 9 7 10 3 42 loci 1 7 10 2 92 taxonom 9 7 10 3 43 tree 1 6 10 2 93 mountain 9 6 10 3 44 northern 1 6 10 2 94 nonnat 9 6 10 3 45 river 1 6 10 2 95 locat 9 6 10 3 46 invas 1 5 10 2 96 indic 9 5 10 3 47 southern 1 5 10 2 97 locus 9 4 10 3 48 threat 1 5 10 2 98 forag 9 3 10 3 49 survey 1 5 10 2 99 monitor 9 3 10 3 50 rang 1 5 10 2 100 freshwat 9 3 10 3 bind 4 2 10 2 52 signal 6 5 10 3 3 cell 3 8 10 2 53 phosphoryl 6 4 10 3 4 membran 2 10 2 54 target 6 3 10 3 5 paper 1 9 10 2 55 fold 6 3 10 3 6 conform 1 6 10 2 56 bilay 6 2 10 3 7 angstrom 1 6 10 2 57 suggest 5 8 10 3 8 molecular 1 6 10 2 58 kinas 5 8 10 3 9 molecul 1 5 10 2 59 play 5 7 10 3 10 induc 1 5 10 2 60 strand 5 6 10 3 11 activ 1 5 10 2 61 coli 5 6 10 3 12


id: cord-131093-osukknqr
type: DNA
entity:
  sea 6 5 10 2 53 popul 1 7 10 2 4 marin 6 10 2 54 gulf 1 7 10 2 5 habitat 5 1 10 2 55 diatom 1 6 10 2 6 water 4 7 10 2 56 pacif 1 6 10 2 7 abund 4 6 10 2 57 larval 1 6 10 2 8 coastal 3 8 10 2 58 reproduct 1 5 10 2 9 benthic 3 6 10 2 59 mediterranean 1 5 10 2 10 ecosystem 3 6 10 2 60 chlorophyl 1 5 10 2 11 river 3 2 10 2 61 mussel 1 5 10 2 12 atlant 3 2 10 2 62 plankton 1 5 10 2 13 fisheri 3 2 10 2 76 attach 1 10 2 27 coat 2 10 2 77 exhibit 1 10 2 28 regener 2 10 2 78 biolog 1 10 2 29 bioactiv 2 10 2 79 gelatin 1 10 2 30 engin 2 10 2 80 synthes 1 10 2 31 load 1 9 10 2 81 sem 1 10 2 32 glycol 1 9 10 2 82 dox 9 9 10 3 33 chitosan 1 9 10 2 83 fluoresc 9 7 10 3 34 encapsul 1 8 10 2 84 extracellular 9 6 10 3 35 osteoblast 1 8 10 2 85 titanium 9 5 10 3 36 biodegrad 1 8 10 2 86 gel 9 4 10 3 37 polymer 1 7 10 2 87 methacryl 9 3 10 3 38 materi 1 7 10 2 88 caprolacton 9 10 3 39 osteogen 1 6 10 2 89 doxorubicin 9 10 3 40 phosphat 1 6 10 2 90 spectroscopi 8 8 10 3 41 viabil 1 6 10 2 91 immobil 8 6 10 3 42 promis 1 6 10 2 92 assay 8 6 10 3 43 fabric 1 2 1 10 2 81 densiti 1 10 2 32 densif 2 10 2 82 hydroxyapatit 1 10 2 33 spectroscopi 2 10 2 83 diseas 1 10 2 34 particl 2 10 2 84 associ 1 10 2 35 size 1 9 10 2 85 character 1 10 2 36 oxid 1 9 10 2 86 paper 1 10 2 37 conclus 1 9 10 2 87 zrb2 9 9 10 3 38 poros 1 8 10 2 88 chemic 9 8 10 3 39 crystallin 1 8 10 2 89 exhibit 9 7 10 3 40 calcin 1 8 10 2 90 b2o3 9 7 10 3 41 structur 1 8 10 2 91 investig 9 7 10 3 42 fabric 1 8 10 2 92 level 9 6 10 3 43 mpa 1 8 10 2 93 mullit 9 6 10 3 44 patient 1 7 10 2 94 pure 9 6 10 3 45 coat 1 6 10 2 95 mol 9 6 10 3 46 morpholog 1 6 10 2 96 mechan 9 5 10 3 47 sio2 1 6 10 2 97 dispers 9 5 10 3 48 zirconia 1 5 10 2 98 vol 9 5 10 3 49 precursor 1 5 10 2 99 silic 9 5 10 3 50 zro2 1 4 10 2 100 dens 9 4 10 3 207 3 5 10 2 51 surfac 6 8 10 3 2 crack 3 10 2 52 activ 6 6 10 3 3 materi 2 8 10 2 53 uniaxi 6 6 10 3 4 stress 2 3 10 2 54 asphalt 6 4 10 3 5 load 2 2 10 2 55 diffract 6 1 10 3 6 specimen 2 1 10 2 56 damag 6 1 10 3 7 tensil 2 1 10 2 57 group 6 10 3 8 strain 1 8 10 2 58 ductil 6 10 3 9 test 1 7 10 2 59 displac 5 9 10 3 10 weld 1 7 10 2 60 popul 5 9 10 3 11 strength 1 7 10 2 61 plate 5 9 10 3 12 deform 1 6 10 2 62 harden 5 5 10 3 13 patient 1 6 10 2 63 cell 5 4 10 3 14 microstructur 1 51 trial 9 7 10 3 2 express 4 10 2 52 stem 9 7 10 3 3 patient 3 9 10 2 53 background 9 5 10 3 4 diseas 3 1 10 2 54 mrna 9 4 10 3 5 treatment 2 8 10 2 55 temperatur 9 3 10 3 6 clinic 2 7 10 2 56 target 9 2 10 3 7 paper 2 7 10 2 57 mous 9 1 10 3 8 protein 2 5 10 2 58 upregul 9 10 3 9 conclus 2 5 10 2 59 week 8 9 10 3 10 induc 2 3 10 2 60 chronic 8 8 10 3 11 mice 2 3 10 2 61 mesenchym 8 8 10 3 12 therapeut 2 2 10 2 62 endotheli 8 7 10 3 13 therapi 2 1 10 2 63 drug 8 4 10 3 14 studi 2 1 10 2 64 downregul 8 3 10 3 15 tissu 2 10 2 65 marker 8 1 10 3 16 tumor 2 10 2 66 liver 7 9 10 3 17 gene 1 9 10 2 67 injuri 7 9 10 3 18 signific 1 9 10 2 68 inflamm 7 9 10 3 19 immun 1 8 10 2 69 bone 7 8 10 3 20 cancer 1 8 10 2 70 administr 7 8 10 3 21 inhibit 1 8 10 2 71 diabet 7 7 10 3 22 human 1 7 10 2 72 control 7 7 10 3 23 vaccin 1 7 10 2 73 inhibitor 7 7 10 3 24 blood 1 7 10 2 74 factor 7 7 10 3 25 rat 1 5 10 2 75 increas 7 7 10 3 26 prolifer 1 5 10 2 76 anim 7 6 10 3 27 vitro 1 5 10 2 77 simul 7 4 10 3 28 receptor 1 5 10 2 78 energi 7 3 10 3 29 associ 1 4 10 2 79 progress 7 1 10 3 30 treat 1 4 10 2 80 vascular 7 10 3 31 vivo 1 3 10 2 81 polymeras 7 10 3 32 level 1 3 10 2 82 surviv 6 9 10 3 33 aim 1 3 10 2 83 interleukin 6 8 10 3 34 may 1 3 10 2 84 inject 6 8 10 3 35 group 1 2 10 2 85 stimul 6 7 10 3 36 apoptosi 1 2 10 2 86 infect 6 7 10 3 37 blot 1 2 10 2 87 normal 6 7 10 3 38 serum 1 2 10 2 88 kinas 6 7 10 3 39 antibodi 1 2 10 2 89 transplant 6 7 10 3 40 dose 1 2 10 2 90 beta 6 7 10 3 41 efficaci 1 2 10 2 91 carcinoma 6 6 10 3 42 assay 1 2 10 2 92 pcr 6 6 10 3 43 activ 1 1 10 2 93 day 6 5 10 3 44 regul 1 1 10 2 94 prevent 6 5 10 3 45 propos 1 10 2 95 cellular 6 4 10 3 46 inflammatori 1 10 2 96 marrow 6 4 10 3 47 antigen 1 10 2 97 follow 6 3 10 3 48 pathway 1 10 2 98 pathogenesi 6 3 10 3 49 mediat 9 9 10 3 99 effect 6 3 10 3 50 cytokin 9 8 10 3 100 stain 6 3 10 3 224 2 1 10 2 72 teach 1 10 2 23 orchestra 2 10 2 73 discours 1 10 2 24 aesthet 2 10 2 74 scholar 1 10 2 25 improvis 1 9 10 2 75 manuscript 1 10 2 26 explor 1 9 10 2 76 way 1 10 2 27 vocal 1 8 10 2 77 theme 9 9 10 3 28 notat 1 8 10 2 78 histor 9 8 10 3 29 singer 1 7 10 2 79 quartet 9 8 10 3 30 audienc 1 7 10 2 80 temperatur 9 7 10 3 31 work 1 7 10 2 81 musicologist 9 6 10 3 32 student 1 6 10 2 82 eighteenth 9 5 10 3 33 musicolog 1 6 10 2 83 narrat 9 5 10 3 34 teacher 1 5 10 2 84 context 9 4 10 3 35 voic 1 5 10 2 85 creat 9 4 10 3 36 school 1 5 10 2 86 increas 9 4 10 3 37 tonal 1 5 10 2 87 musicianship 9 4 10 3 38 contemporari 1 surfac 3 9 10 2 54 high 1 10 2 5 film 2 9 10 2 55 carbon 1 10 2 6 devic 2 6 10 2 56 background 1 10 2 7 nanostructur 2 5 10 2 57 tio2 9 8 10 3 8 layer 2 2 10 2 58 assess 9 8 10 3 9 microscopi 2 2 10 2 59 risk 9 8 10 3 10 metal 2 2 10 2 60 particl 9 6 10 3 11 graphen 2 2 10 2 61 selfassembl 9 6 10 3 12 properti 8 2 10 3 9 accid 3 1 10 2 59 dosimet 8 2 10 3 10 code 3 10 2 60 radon 8 2 10 3 11 mev 2 9 10 2 61 co60 8 1 8 10 2 89 depress 9 9 10 3 40 team 1 7 10 2 90 compet 9 9 10 3 41 manag 1 7 10 2 91 understand 9 6 10 3 42 perceiv 1 7 10 2 92 distress 9 5 10 3 43 mental 1 7 10 2 93 paramet 9 5 10 3 44 life 1 6 10 2 94 focus 9 3 10 3 45 unit 1 6 10 2 95 servic 9 2 10 3 46 studi 1 6 10 2 96 infant 9 2 10 3 47 experienc 1 5 10 2 97 live 9 2 10 3 48 famili 1 5 10 2 98 psycholog 9 1 10 3 49 midwiv 1 5 10 2 99 assess 9 1 10 3 50 find 1 5 10 2 100 conduct 9 10 3 women 2 1 10 1 51 mother 2 1 10 2 2 pregnanc 1 6 10 1 52 reproduct 2 1 10 2 3 conclus 1 3 10 1 53 prenat 2 10 2 4 gestat 1 10 1 54 placenta 1 9 10 2 5 object 8 9 10 2 55 intervent 1 9 10 2 6 matern 7 9 10 2 56 woman 1 9 10 2 7 birth 7 3 10 2 57 method 1 9 10 2 8 outcom 5 9 10 2 58 ultrasound 1 9 10 2 9 fetal 5 9 10 2 59 care 1 9 10 2 10 vagin 4 8 10 2 60 contracept 1 9 10 2 11 obstetr 4 8 10 2 61 underw 1 9 10 2 12 ovarian 4 7 10 2 62 hormon 1 numer 3 7 10 2 54 age 1 10 2 5 turbul 3 7 10 2 55 magnetohydrodynam 1 10 2 6 veloc 3 6 10 2 56 steadi 9 7 10 3 7 reynold 2 8 10 2 57 cyclotron 9 6 10 3 8 equat 2 8 10 2 58 motion 9 6 10 3 9 particl 2 7 10 2 59 energi 9 4 10 3 10 wave 2 6 10 2 60 analyt 9 2 10 3 11 tokamak 2 6 10 2 61 navier 9 2 10 3 12 instabl 2 5 10 2 62 forc 9 2 10 3 13 simul 2 3 10 2 63 transit 9 10 3 14 field 2 1 10 2 64 divertor 9 10 3 15 regim 2 10 2 65 convect 8 9 10 3 16 vortic 2 10 2 66 propag 8 9 10 3 17 discharg 2 10 2 67 activ 8 7 10 3 18 patient 1 collis 4 10 2 59 spin 1 10 2 10 gev 3 9 10 2 scalar 7 3 10 2 51 collis 1 9 10 2 2 quark 6 4 10 2 52 conclus 1 9 10 2 3 higg 5 9 10 2 53 increas 1 9 10 2 4 gaug 5 9 10 2 54 string 1 9 10 2 5 lhc 5 9 10 2 55 black 1 9 10 2 6 cosmolog 5 3 10 2 56 proton 1 8 10 2 7 gev 5 2 10 2 57 nucleon 1 8 10 2 8 boson 5 2 10 2 induc 3 7 10 2 53 pathway 1 1 10 2 4 rat 3 6 10 2 54 studi 1 10 2 5 express 3 10 2 55 base 1 10 2 6 increas 3 10 2 56 inhibitor 1 10 2 7 paper 2 7 10 2 57 signal 1 10 2 8 receptor 2 5 10 2 58 kinas 1 10 2 9 regul 2 4 10 2 59 glucos 9 9 10 3 10 respons 2 4 10 2 60 propos 9 7 10 3 11 physiolog 2 4 10 2 61 mechan 9 5 10 3 12 protein 2 4 10 2 articl 3 4 10 2 56 temperatur 1 10 2 7 social 3 4 10 2 57 trade 1 10 2 8 polit 3 3 10 2 58 labour 9 9 10 3 9 urban 3 1 10 2 59 hous 9 8 10 3 10 economi 2 1 10 2 72 pollin 1 10 2 23 patient 2 10 2 73 auxin 1 10 2 24 breed 1 9 10 2 74 model 1 10 2 25 isol 1 9 10 2 75 biomass 9 9 10 3 26 genet 1 9 10 2 76 oryza 9 9 10 3 27 accumul 1 9 10 2 77 dri 9 7 10 3 28 genus 1 9 10 2 78 morpholog 9 7 10 3 29 rice 1 8 10 2 79 aba 9 6 10 3 30 veget 1 7 10 2 80 taxonom 9 5 10 3 31 grown 1 7 10 2 81 marker 9 5 10 3 32 tree 1 7 10 2 82 weed 9 5 10 3 33 chloroplast 1 6 10 2 83 infloresc 9 4 10 3 34 photosynthesi 1 6 10 2 84 antioxid 9 2 10 3 35 transgen 1 6 10 2 85 forest 9 1 10 3 36 drought 1 6 10 2 86 product 9 1 10 3 37 wheat 1 6 10 2 87 comput 9 1 10 3 38 mutant 1 5 10 2 88 maiz 9 10 3 39 transcript 1 5 10 2 89 plastid 9 10 3 40 wild 1 5 10 2 90 qtl 9 10 3 41 toler 1 5 10 2 91 greenhous 8 9 10 3 42 pollen 1 argu 9 3 10 2 57 blur 2 10 2 8 emili 7 9 10 2 58 letter 2 10 2 9 literari 7 5 10 2 59 artist 2 10 2 10 text 7 4 10 2 60 pen 2 10 2 11 lyric 6 3 10 2 61 wife 2 10 2 implic 3 9 10 2 55 perspect 9 6 10 3 6 psycholog 3 4 10 2 56 negat 9 3 10 3 7 examin 3 4 10 2 57 offend 9 1 10 3 8 perceiv 3 2 10 2 58 temperatur 9 10 3 9 relationship conclus 7 5 10 2 54 relat 2 10 2 5 addict 6 7 10 2 55 month 2 10 2 6 drug 6 7 10 2 56 gambler 1 9 10 2 7 smoke 6 5 10 2 57 male 1 9 10 2 8 particip 6 2 10 2 58 youth 1 9 10 2 9 abus 6 1 10 2 59 misus 1 9 10 2 10 abstin 5 8 10 2 60 report 1 9 10 2 11 smoker 5 3 10 2 61 social 1 9 10 2 12 background 1 6 10 1 51 nrtl 9 9 10 3 2 temperatur 8 8 10 2 52 pipe 9 9 10 3 3 thermal 7 3 10 2 53 calcul 9 8 10 3 4 flow 6 10 2 54 mass 9 6 10 3 5 transfer 5 1 10 2 55 age 9 6 10 3 6 cool 4 3 10 2 56 obtain 9 5 10 3 7 fluid 4 1 10 2 57 protein 9 5 10 3 8 pressur 4 10 2 58 isotherm 9 5 10 3 9 experiment 3 7 10 2 59 drop 9 5 10 3 10 convect traffic 8 4 10 2 52 batteri 9 7 10 3 3 paper 6 4 10 2 53 demand 9 6 10 3 4 road 5 8 10 2 54 plan 9 1 10 3 5 travel 4 10 2 55 scheme 9 10 3 6 transport 3 3 10 2 56 asphalt 9 10 3 7 propos 2 9 10 2 57 intersect 8 9 10 3 8 car 2 9 10 2 58 crash 1 6 10 2 97 coinfect 9 9 10 3 48 pathogen 1 5 10 2 98 stool 9 9 10 3 49 countri 1 5 10 2 99 larval 9 9 10 3 50 area 1 5 10 2 100 diagnosi 9 7 10 3 313 social 3 5 10 2 59 draw 1 10 2 10 metropolitan 3 4 10 2 60 suburban 1 10 2 11 polit 3 1 10 2 61 rural 1 10 2 12


id: cord-131093-osukknqr
type: PROTEIN
entity:
  articl prostat 7 4 10 2 56 proteinuria 2 10 2 7 bladder 6 6 10 2 57 treat 2 10 2 8 dialysi 5 9 10 2 58 nephropathi 2 10 2 9 outcom 5 3 10 2 59 dysfunct 2 10 2 10 glomerular replic 8 7 10 2 54 entri 1 6 10 2 5 hiv 8 7 10 2 55 nucleotid 1 6 10 2 6 host 6 6 10 2 56 immunodefici 1 6 10 2 7 protein 6 5 10 2 57 titer 1 6 10 2 8 rna 6 3 10 2 58 inhibit 1 6 10 2 9 cell 6 1 10 2 59 mediat 1 6 10 2 10 antivir 5 8 10 2 60 epitop 1 6 10 2 11 genom 5 5 10 2 61 hbv 1 6 10 2 12


id: cord-131093-osukknqr
type: GGP
entity:
  anthocyanin 6 1 10 3 43 nutrit 9 7 10 3 93 bean 6 1 10 3 44 dairi 9 6 10 3 94 tillag 6 10 3 45 soybean 9 5 10 3 95 rumin 6 10 3 46 graze 9 5 10 3 96 winter 5 9 10 3 47 biomass 9 3 10 3 97 potato 5 8 10 3 48 cattl 9 2 10 3 98 rumen 5 8 10 3 49 manur 9 1 10 3 99 compound 5 8 10 3 50 trait 8 5 10 3


id: cord-131093-osukknqr
type: GGP
entity:
  growth 2 10 2 84 differ 9 9 10 3 35 genet 1 9 10 2 85 manag 9 9 10 3 36 shoot 1 9 10 2 86 three 9 7 10 3 37 patient 1 9 10 2 87 four 9 7 10 3 38 field 1 8 10 2 88 manur 9 6 10 3 39 qtl 1 8 10 2 89 grower 9 6 10 3 40 veget 1 8 10 2 90 qualiti 9 5 10 3 41 grow 1 8 10 2 91 tomato 9 4 10 3 42 nutrient 1 8 10 2 92 barley 9 4 10 3 43 speci 1 8 10 2 93 chromosom 9 2 10 3 44 triticum 1 7 10 2 94 method 9 1 10 3 45 leav 1 7 10 2 95 popul 9 10 3 46 water 1 7 10 2 96 treatment 8 9 10 3 47 inocul 1 5 10 2 97 spring 8 9 10 3 48 paper 1 5 10 2 98 suscept 8 8 10 3 49 nitrogen 1 5 10 2 99 fresh 8 7 10 3 50 orchard 1 5 10 2 100 progeni 8 7 10 3 2 2 10 2 87 cavernosum 1 10 2 38 spermatogen 2 10 2 88 glutathion 1 10 2 39 intracytoplasm 1 9 10 2 89 superoxid 9 8 10 3 40 normal 1 9 10 2 90 assay 9 8 10 3 41 divid 1 9 10 2 91 express 9 7 10 3 42 level 1 9 10 2 92 oestradiol 9 7 10 3 43 iief 1 8 10 2 93 fragment 9 6 10 3 44 asthenozoosperm 1 7 10 2 94 albuginea 9 6 10 3 45 decreas 1 7 10 2 95 simul 9 5 10 3 46 normozoosperm 1 7 10 2 96 stimul 9 5 10 3 47 cauda 1 6 10 2 97 ielt 9 5 10 3 48 leydig 1 6 10 2 98 lutein 9 5 10 3 49 serum 1 6 10 2 99 method 9 5 10 3 50 icsi 1 6 10 2 100 peroxid 9 5 10 3 anthropolog 4 7 10 2 52 radiocarbon 9 8 10 3 3 ethnograph 4 5 10 2 53 stone 9 8 10 3 4 social 4 3 10 2 54 live 9 7 10 3 5 polit 3 1 10 2 55 chronolog 9 6 10 3 6 cultur 3 1 10 2


id: cord-131093-osukknqr
type: GGP
entity:
  evid 1 8 10 2 84 iron 1 10 2 35 cal 1 8 10 2 85 town 1 10 2 36 tomb 1 8 10 2 86 decor 1 10 2 37 effect 1 8 10 2 87 record 1 10 2 38 context 1 7 10 2 88 conclus 9 8 10 3 39 remain 1 6 10 2 89 taphonom 9 8 10 3 40 mediev 1 6 10 2


id: cord-131093-osukknqr
type: GGP
entity:
  cell 1 2 10 2 83 histori 6 9 10 3 34 tradit 1 2 10 2 84 detect 6 8 10 3 35 typolog 1 2 10 2 85 decreas 6 7 10 3 36 sustain 1 1 10 2 86 idea 6 7 10 3 37 twentieth 1 10 2 87 new 6 7 10 3 38 conserv 9 7 10 3 88 nineteenth 6 6 10 3 39 earthen 9 6 10 3 89 technolog 6 6 10 3 40 digit 9 6 10 3 90 induc 6 6 10 3 41 preserv 9 5 10 3 91 creation 6 6 10 3 42 conclus 9 4 10 3 92 acid 6 6 10 3 43 show 9 3 10 3 93 higher 6 5 10 3 44 residenti 9 2 10 3 94 survey 6 5 10 3 45 villag 9 1 10 3 95 dwell 6 4 10 3 46 environ 9 10 3 96 way 6 3 10 3 47 today 8 9 10 3 97 social 6 3 10 3


id: cord-131093-osukknqr
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  analysi 9 1 10 3 39 suggest 1 8 10 2 89 previous 9 10 3 40 molecular 1 7 10 2 90 evolut 8 9 10 3 41 divers 1 4 10 2 51 radar 1 7 10 2 2 rock 8 5 10 2 52 northern 1 6 10 2 3 mantl 6 9 10 2 53 constrain 1 6 10 2 4 crust 5 2 10 2 54 model 1 6 10 2 5 crustal 4 9 10 2 55 orogen 1 6 10 2 6 earthquak 4 7 10 2 56 composit 1 6 10 2 7 zone 4 6 10 2 57 conclus 1 5 10 2 8 isotop 4 5 10 2 58 belt 1 5 10 2 9 subduct 4 2 10 2 59 upper 1 5 10 2 10 tecton 4 1 10 2 60 near 1 5 10 2 11 geolog 4 10 2 61 emplac 1 5 10 2 12 lithospher 4 10 2 62 estim 1 5 10 2 13 earth 3 9 10 2 63 fluid 1 1 9 10 2 70 livelihood 1 10 2 21 explor 1 9 10 2 71 clinic 1 10 2 22 actor 1 9 10 2 72 world 1 10 2 23 territori 1 8 10 2 73 cultur 1 10 2 24 region 1 8 10 2 74 result 1 10 2 25 space 1 8 10 2 75 develop 9 9 10 3 26 patient 1 7 10 2 76 particular 9 9 10 3 27 communiti 1 7 10 2 77 emerg 9 7 10 3 28 context 1 7 10 2 78 ecolog 9 7 10 3 29 focus 1 7 10 2 79 question 9 6 10 3 30 public 1 7 10 2 80 conceptu 9 6 10 3 31 discours 1 6 10 2 81 concept 9 3 10 3 32 paper 1 6 10 2 82 residenti 9 3 10 3 33 socio 1 6 10 2 83 protein 9 1 10 3 34 nation 1 6 10 2 84 map 9 10 3 35 plan 1 6 10 2 85 within 8 9 10 3 36 understand 1 6 10 2 86 resid 8 9 10 3 37 engag 1 5 10 2 87 natur 8 glacial 4 2 10 2 56 topograph 1 6 10 2 7 spatial 4 10 2 57 eastern 1 6 10 2 8 land 3 9 10 2 58 south 1 6 10 2 9 glacier 3 6 10 2 59 geograph 1 6 10 2 10 pleistocen 3 4 10 2 60 period 1 6 10 2 11 veget 3 3 10 2 61 stratigraph 1 5 10 2 12 sea 3 3 10 2 62 season 1 5 10 2 13 river 3 1 10 2 63 east 1 5 10 2 14 region 3 3 6 10 2 72 method 2 10 2 23 sandston 3 6 10 2 73 geochemistri 2 10 2 24 metamorph 3 5 10 2 74 clastic 2 10 2 25 jurass 3 4 10 2 75 grain 2 10 2 26 middl 3 3 10 2 76 ocean 2 10 2 27 continent 3 3 10 2 77 paleozo 1 9 10 2 28 shallow 3 3 10 2 78 uplift 1 9 10 2 29 crust 3 2 10 2 79 form 1 9 10 2 30 earli 3 2 10 2 80 date 1 9 10 2 31 north 3 2 10 2 81 siliciclast 1 9 10 2 32 fossil 3 2 10 2 82 fauna 1 9 10 2 33 southern 3 2 10 2 83 eocen 1 9 10 2 34 limeston 3 1 10 2 84 biostratigraph 1 9 10 2 35 northern 3 10 2 85 cambrian 1 9 10 2 36 interpret 3 10 2 86 occur 1 8 10 2 37 belt 3 10 2 87 coeval 1 8 10 2 38 sea 3 10 2 88 western 1 8 10 2 39 orogen 2 9 10 2 89 terran 1 8 10 2 40 eastern 2 9 10 2 90 central 1 dementia 7 5 10 2 54 caregiv 1 6 10 2 5 cognit 6 9 10 2 55 frail 1 6 10 2 6 adult 6 5 10 2 56 adjust 1 5 10 2 7 conclus 6 10 2 57 daili 1 5 10 2 8 particip 5 7 10 2 58 comorbid 1 5 10 2 9 geriatr 5 2 10 2 59 result 1 5 10 2 10 alzheim 5 10 2 60 memori 1 1 9 10 2 93 includ 1 10 2 44 symptom 1 9 10 2 94 sex 1 10 2 45 men 1 9 10 2 95 walk 1 10 2 46 signific 1 9 10 2 96 brain 1 10 2 47 cohort 1 8 10 2 97 odd 1 10 2 48 popul 1 8 10 2 98 logist 1 10 2 49 background 1 8 10 2 99 interview 9 9 10 3 50 group 1 8 10 2 100 amyloid 9 9 10 3 sustain 3 7 10 2 52 system 7 2 10 3 3 environment 3 3 10 2 53 oper 7 2 10 3 4 renew 2 7 10 2 54 ghg 6 9 10 3 5 co2 2 3 10 2 55 yield 6 8 10 3 6 product 2 3 10 2 56 develop 6 7 10 3 7 econom 2 2 10 2 57 gene 6 7 10 3 8 fuel 2 2 10 2 58 plant 6 5 10 3 9 patient 1 9 10 2 59 biodiesel 6 5 10 3 10 wast 1 8 10 2 60 climat 6 5 10 3 11 turbin 1 7 10 2 61 solvent 6 4 10 3 12 carbon 1 6 10 2 62 age 6 3 10 3 13 catalyst 1 6 10 2 63 express 6 3 10 3 14 solar 1 6 10 2 64 eco 6 2 10 3 15 wind 1 5 10 2 65 catalyt 6 1 10 3 16 biomass 1 5 10 2 66 save 6 10 3 17 electr 1 5 10 2 67 temperatur 5 8 10 3 18 effici 1 1 6 10 2 92 expenditur 9 9 10 3 43 year 1 6 10 2 93 payment 9 9 10 3 44 regress 1 6 10 2 94 address 9 9 10 3 45 data 1 6 10 2 95 live 9 8 10 3 46 incom 1 5 10 2 96 satisfact 9 8 10 3 47 background 1 5 10 2 97 identifi 9 8 10 3 48 access 1 5 10 2 98 report 9 8 10 3 49 implement 1 5 10 2 99 receiv 9 7 10 3 50 ill 1 5 10 2 100 energi 9 5 10 3 philosoph 3 6 10 2 55 polit 1 10 2 6 ethic 3 1 10 2 56 context 9 6 10 3 7 result 3 10 2 57 discuss 9 6 10 3 8 argument 2 9 10 2 58 decreas 9 6 10 3 9 scientist 2 8 10 2 59 british 9 6 10 3 10 articl 2 5 10 2 60 higher 9 4 10 3 11 claim 2 3 10 2 61 draw 9 4 10 3 12 philosophi 2 3 10 2 62 obtain 9 3 10 3 13 epistem 2 2 10 2 63 measur 9 2 10 3 14 view 2 10 2 64 darwin 9 2 10 3 15 histori 2 10 2 65 contemporari 9


id: cord-131093-osukknqr
type: CHEMICAL
entity:
  oblig 9 4 10 3 6 polit 2 9 10 2 56 surfac 9 4 10 3 7 moral 2 8 10 2 57 individu 9 3 10 3 8 welfar 2 6 10 2 The Meaning of Meaning A


id: cord-328252-dk54w8z9
type: GGP
entity:
  RIG I like receptors hide mask hit Global regional and national causes of child mortality in 2000 13 with projections


id: cord-328252-dk54w8z9
type: ORG
entity:
  the Induction of Innate Immunity and Excessive Inflammation During Respiratory Viral Infections Innate Immunity to Respiratory Infection


id: cord-328252-dk54w8z9
type: ORG
entity:
  Respiratory Syncytial Virus and Cellular Stress Responses Impact on Replication and Physiopathology Middle East Respiratory Coronavirus Accessory Protein


id: cord-328252-dk54w8z9
type: ORG
entity:
  Identification of Respiratory Syncytial Virus Nonstructural Protein 2 Residues Essential for Exploitation of the Host Ubiquitin System and Inhibition of Innate Immune Responses


id: cord-328252-dk54w8z9
type: WORK_OF_ART
entity:
  Upregulated in Respiratory Syncytial Virus Infection and Reduces Virus Growth through Protein ISGylation


id: cord-328252-dk54w8z9
type: DISEASE
entity:
  influenza A virus NS1 interacting protein that antagonizes the inhibitory role of NS1 on PKR phosphorylation Foot and Mouth Disease


id: cord-328252-dk54w8z9
type: DISEASE
entity:
  acute respiratory syndrome coronavirus papain like protease Nidovirus papain like proteases multifunctional


id: cord-319501-a2x1hvkk
type: PROTEIN
entity:
  downstream effectors tumor necrosis factor receptor associated factor 3 TRAF3 TANK binding kinase 1 TBK1


id: cord-346916-jj4l9ydl
type: GGP
entity:
  p38 mitogen activated protein kinase MAPK c Jun N terminal kinase JNK signal transducer and activator of transcription 1 and 3 STAT1


id: cord-327000-oyg3oyx1
type: LAW
entity:
  PEDV The Accessory Protein ORF3 Contributes to Porcine Epidemic Diarrhea Virus Replication by Direct Binding


id: cord-327000-oyg3oyx1
type: WORK_OF_ART
entity:
  Localization and Effect on Type I Interferon Response of Porcine Epidemic Diarrhea Virus Nsp7 Host Factors in Coronavirus Replication Coronavirus Endoribonuclease Activity in Porcine Epidemic Diarrhea Virus


id: cord-327000-oyg3oyx1
type: CHEMICAL
entity:
  N genes Figure 1 39 40 41 The N terminal ORF1a and ORF1b encode two large replicase polyprotein precursors pp1a and pp1ab


id: cord-307914-lgprrwee
type: WORK_OF_ART
entity:
  The Roles of Type I Interferon in Bacterial Infection Intracellular Nucleic Acid Sensing Triggers Necroptosis through Synergistic Type I IFN


id: cord-355839-o0m71kvw
type: PROTEIN
entity:
  nuclear factor kappa B kinase subunit epsilon IRF3 interferon regulatory factor 3 IRF7 interferon regulatory factor 7 JNK c Jun N terminal kinase MAPK mitogen activated protein kinase


id: cord-355839-o0m71kvw
type: PROTEIN
entity:
  receptor TRAF3 tumor necrosis factor receptor associated factor 3 TRAF6 tumor necrosis factor receptor associated factor 6 TRAM toll


id: cord-355839-o0m71kvw
type: GGP
entity:
  kappa B kinase subunit epsilon IRF3 interferon regulatory factor 3 IRF7 interferon regulatory factor 7 JNK c Jun N terminal kinase MAPK mitogen activated protein kinase MAVS mitochondrial


id: cord-355839-o0m71kvw
type: ORG
entity:
  Immunopharmacol Identification of Respiratory Syncytial Virus Nonstructural Protein 2 Residues Essential for Exploitation of the Host Ubiquitin System and Inhibition of Innate Immune Responses Mutation


id: cord-355839-o0m71kvw
type: CHEMICAL
entity:
  IFN interferon IFNAR interferon alpha beta receptor IKKε inhibitor of nuclear factor kappa B kinase subunit epsilon IPO13 importin 13 IRF3 interferon regulatory factor 3 ISG IFN


id: cord-303189-ktl4jw8v
type: PROTEIN
entity:
  Interferon gamma interferoninducible protein 16 IFI16 STING extrachromosomal histone H2B leucine rich repeat


id: cord-303189-ktl4jw8v
type: CHEMICAL
entity:
  hepatitis C virus NS3 4A proteolytic cleavage Cleavage of mitochondrial antiviral signaling protein in the liver of


id: cord-313138-y485ev30
type: GGP
entity:
  Comp Immunol DOI 10 1016 j dci 2013 04 010 sha c8f7838853a28b0618da802dd333f6eeaa1f5fe8 doc_id 313138 cord_uid y485ev30 Birds


id: cord-313138-y485ev30
type: GGP
entity:
  IFIT5 XM_003208028 1 zebra finch IFIT5 XM_002188552 1 human IFIT1 NM_001270927 1 mouse IFIT1 NM_008331 3 human IFIT2


id: cord-313138-y485ev30
type: GGP
entity:
  avian Toll like receptor TLR system implications for transmission and control of bird borne zoonoses The LILR family modulators of innate and adaptive immune


id: cord-319729-6lzjhn8j
type: ORG
entity:
  Lab Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by


# bib

id: cord-000125-uvf5qzfd
author: Kenworthy, Rachael
date: 2009-09-03
txt: ./txt/cord-000125-uvf5qzfd.txt
cache: ./cache/cord-000125-uvf5qzfd.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770676/
doi: 10.1093/nar/gkp714
summary:
  The interaction between a PAMP and a PRR triggers activation of the interferon (IFN) pathway in mammalian cells, which significantly changes the gene-expression profile in the cells and contributes to the well-documented off-target effect of RNAi. IFN induction is especially problematic in antiviral studies employing RNAi, where the antiviral effect of IFN must be distinguished from that of RNAi. Typical IFN-inducing structure patterns include dsRNA of certain length, single-stranded RNA (ssRNA) containing 5 0 -triphosphates (5 0 -ppp), the dsRNA analogue polyinosinic-polycytidylic acid (poly I:C), and certain dsDNA molecules. Mammalian expression plasmids encoding each of these proteins, as well as the dominant negative (DN) mutants of RIG-I and MDA5, were transfected into 293FT cells with shRNAs and an IFN-b promoter reporter construct.

title:
  Short-hairpin RNAs delivered by lentiviral vector transduction trigger RIG-I-mediated IFN activation

abstract:
  Activation of the type I interferon (IFN) pathway by small interfering RNA (siRNA) is a major contributor to the off-target effects of RNA interference in mammalian cells. While IFN induction complicates gene function studies, immunostimulation by siRNAs may be beneficial in certain therapeutic settings. Various forms of siRNA, meeting different compositional and structural requirements, have been reported to trigger IFN activation. The consensus is that intracellularly expressed short-hairpin RNAs (shRNAs) are less prone to IFN activation because they are not detected by the cell-surface receptors. In particular, lentiviral vector-mediated transduction of shRNAs has been reported to avoid IFN response. Here we identify a shRNA that potently activates the IFN pathway in human cells in a sequence- and 5′-triphosphate-dependent manner. In addition to suppressing its intended mRNA target, expression of the shRNA results in dimerization of interferon regulatory factor-3, activation of IFN promoters and secretion of biologically active IFNs into the extracellular medium. Delivery by lentiviral vector transduction did not avoid IFN activation by this and another, unrelated shRNA. We also demonstrated that retinoic-acid-inducible gene I, and not melanoma differentiation associated gene 5 or toll-like receptor 3, is the cytoplasmic sensor for intracellularly expressed shRNAs that trigger IFN activation.


id: cord-001129-gi2kswai
title: Positive Evolutionary Selection On the RIG-I-Like Receptor Genes in Mammals
author: Lemos de Matos, Ana
date: 2013-11-27
txt: ./txt/cord-001129-gi2kswai.txt
cache: ./cache/cord-001129-gi2kswai.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842351/
doi: 10.1371/journal.pone.0081864
summary:
  Because viruses are responsible for a great number of severe and lethal diseases, together with the important role that RLRs play in mammalian innate immune system, we expect that RIG-I, MDA5 and LGP2 genes may have been under intense selective pressures in all mammals. Evidence for positive selection on mammalian orthologous for RIG-I ( Figure S7 ), MDA5 ( Figure S8 ) and LGP2 ( Figure S9 ) genes was detected using PAML package [54, 55] site-specific models M1a versus M2a and M7 versus M8. (C) Positively-selected codons are exhibited in the table and numbered according to the mammalian LGP2 deduced protein sequences alignment ( Figure S6 downstream RIG-I and MDA5 signaling, which implies functional constraints, the observed variability across species can be perceived as a great structural plasticity for mammalian CARDs. The helicase domain in the RLR family is generally described as exhibiting affinity for dsRNA [78] .

abstract:
  The mammalian RIG-I-like receptors, RIG-I, MDA5 and LGP2, are a family of DExD/H box RNA helicases responsible for the cytoplasmic detection of viral RNA. These receptors detect a variety of RNA viruses, or DNA viruses that express unusual RNA species, many of which are responsible for a great number of severe and lethal diseases. Host innate sentinel proteins involved in pathogen recognition must rapidly evolve in a dynamic arms race with pathogens, and thus are subjected to long-term positive selection pressures to avoid potential infections. Using six codon-based Maximum Likelihood methods, we were able to identify specific codons under positive selection in each of these three genes. The highest number of positively selected codons was detected in MDA5, but a great percentage of these codons were located outside of the currently defined protein domains for MDA5, which likely reflects the imposition of both functional and structural constraints. Additionally, our results support LGP2 as being the least prone to evolutionary change, since the lowest number of codons under selection was observed for this gene. On the other hand, the preponderance of positively selected codons for RIG-I were detected in known protein functional domains, suggesting that pressure has been imposed by the vast number of viruses that are recognized by this RNA helicase. Furthermore, the RIG-I repressor domain, the region responsible for recognizing and binding to its RNA substrates, exhibited the strongest evidence of selective pressures. Branch-site analyses were performed and several species branches on the three receptor gene trees showed evidence of episodic positive selection. In conclusion, by looking for evidence of positive evolutionary selection on mammalian RIG-I-like receptor genes, we propose that a multitude of viruses have crafted the receptors biological function in host defense, specifically for the RIG-I gene, contributing to the innate species-specific resistance/susceptibility to diverse viral pathogens.


id: cord-002689-qakbp4dz
title: Viral inhibitions of PACT-induced RIG-I activation
author: Brisse, Morgan
date: 2017-07-03
txt: ./txt/cord-002689-qakbp4dz.txt
cache: ./cache/cord-002689-qakbp4dz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617381/
doi: 10.18632/oncotarget.18928
abstract: nan
summary:
  Influenza virus NS1, MERS-CoV 4a, herpesvirus HSV1 Us11, and ebola virus VP35 proteins have all been shown to directly disrupt the interaction between RIG-I and PACT, and hence blocks the ability of PACT to activate RIG-I (4-7). All these viral proteins have RNA binding capabilities, yet it isn''t clear from the published reports whether dsRNA is absolutely required to activate RIG-I via PACT induction. When HEK293T cells were transfected with 4a from dsRNA binding MERS-CoV and bCoV-HKU5 and non-dsRNA binding bCoV-HKU4, the IFNβ promoter activity was suppressed in the dsRNA binding 4a expressing cells but was not affected in the non-dsRNA 4a expressing cells, indicating that dsRNA binding is necessary for inhibition of IFN1 production [5] . Like influenza NS1 and MERS-CoV 4a proteins, Us11 protein of HSV1 is a dsRNA binding protein and has been shown to associate with PACT, PKR, MDA5 and RIG-I in addition to 2′,5′-oligoadenylate synthetase (OAS). These known viral proteins have RNA-binding properties, yet it still isn''t entirely clear whether RNA binding is an absolute requirement to inhibit PACT-induced RIG-I activation.


id: cord-007382-5kb16qb7
title: Nucleic Acid Immunity
author: Hartmann, G.
date: 2016-12-15
txt: ./txt/cord-007382-5kb16qb7.txt
cache: ./cache/cord-007382-5kb16qb7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112058/
doi: 10.1016/bs.ai.2016.11.001
summary:
  With the additions of RNAi and the CRISPR/Cas system, specific nucleases including the restriction-modification (R-M) systems, and antiviral effector proteins partially discovered only recently in the context of rare hereditary inflammatory diseases, the new concept of nucleic acid immunity evolves. While innate nucleic acid immune-sensing receptors elicit antiviral signaling pathways, a number of nucleic acid-detecting effector proteins (viral restriction factors, e.g., PKR, ADAR1, IFIT1) directly detect and restrict nucleic acid function and replication. Another member of the RIG-I-like helicase family of receptors is MDA5 which was found to be responsible for the long sought after type I IFN-inducing activity of cytosolic long double-stranded RNA including poly(I:C) . Extrinsic effects inside the same cell include degradation of the nucleic acid (e.g., RNase L activated by 2 0 -5 0 -OA generated by OAS1 upon binding of long double-stranded RNA).

abstract:
  Organisms throughout biology need to maintain the integrity of their genome. From bacteria to vertebrates, life has established sophisticated mechanisms to detect and eliminate foreign genetic material or to restrict its function and replication. Tremendous progress has been made in the understanding of these mechanisms which keep foreign or unwanted nucleic acids from viruses or phages in check. Mechanisms reach from restriction-modification systems and CRISPR/Cas in bacteria and archaea to RNA interference and immune sensing of nucleic acids, altogether integral parts of a system which is now appreciated as nucleic acid immunity. With inherited receptors and acquired sequence information, nucleic acid immunity comprises innate and adaptive components. Effector functions include diverse nuclease systems, intrinsic activities to directly restrict the function of foreign nucleic acids (e.g., PKR, ADAR1, IFIT1), and extrinsic pathways to alert the immune system and to elicit cytotoxic immune responses. These effects act in concert to restrict viral replication and to eliminate virus-infected cells. The principles of nucleic acid immunity are highly relevant for human disease. Besides its essential contribution to antiviral defense and restriction of endogenous retroelements, dysregulation of nucleic acid immunity can also lead to erroneous detection and response to self nucleic acids then causing sterile inflammation and autoimmunity. Even mechanisms of nucleic acid immunity which are not established in vertebrates are relevant for human disease when they are present in pathogens such as bacteria, parasites, or helminths or in pathogen-transmitting organisms such as insects. This review aims to provide an overview of the diverse mechanisms of nucleic acid immunity which mostly have been looked at separately in the past and to integrate them under the framework nucleic acid immunity as a basic principle of life, the understanding of which has great potential to advance medicine.


id: cord-007689-0vpp3xdl
title: Beyond Double-Stranded RNA-Type I IFN Induction by 3pRNA and Other Viral Nucleic Acids
author: Schlee, M.
date: 2007
txt: ./txt/cord-007689-0vpp3xdl.txt
cache: ./cache/cord-007689-0vpp3xdl.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7120510/
doi: 10.1007/978-3-540-71329-6_11
summary:
  Since the discovery of type I IFNs in 1957, long double-stranded RNA formed during replication of many viruses was thought to be responsible for type I IFN induction, and for decades double-stranded RNA-activated protein kinase (PKR) was thought to be the receptor. It now became evident that not PKR but two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, and two cytosolic helicases, RIG-I and MDA-5, are responsible for the majority of type I IFNs induced upon recognition of viral nucleic acids. Based on the recent progress in the field, we now know that TLR7, TLR9, and RIG-I do not require long double-stranded RNA for type I IFN induction. These two cytosolic receptors are then responsible for the second and prolonged wave of type I IFN production and for the induction of apoptosis of virally infected cells. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3

abstract:
  Production of type I IFN is the key response to viral infection. Since the discovery of type I IFNs in 1957, long double-stranded RNA formed during replication of many viruses was thought to be responsible for type I IFN induction, and for decades double-stranded RNA-activated protein kinase (PKR) was thought to be the receptor. Recently, this picture has dramatically changed. It now became evident that not PKR but two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, and two cytosolic helicases, RIG-I and MDA-5, are responsible for the majority of type I IFNs induced upon recognition of viral nucleic acids. In this review, we focus on the molecular mechanisms by which those innate immune receptors detect viral infection. Based on the recent progress in the field, we now know that TLR7, TLR9, and RIG-I do not require long double-stranded RNA for type I IFN induction.


id: cord-131093-osukknqr
title: Informational Space of Meaning for Scientific Texts
author: Suzen, Neslihan
date: 2020-04-28
txt: ./txt/cord-131093-osukknqr.txt
cache: ./cache/cord-131093-osukknqr.txt
extension: .txt
mime: text/plain
url: https://arxiv.org/pdf/2004.13717v1.pdf
doi: nan
summary:
  We introduce the Meaning Space, in which the meaning of a word is represented by a vector of Relative Information Gain (RIG) about the subject categories that the text belongs to, which can be obtained from observing the word in the text. Informational Space of Meaning for Scientific Texts Poibeau and Korhonen then purposed a model in which latent space is used to identify important dimensions for a context and adapt to vector of words constructed by the dependency relations with window-based context words [69]. This technique allowed us to represent each word by a distribution of numerical values over categories and meaning in text through a vector space model, that is, quantifying of meaning. Therefore, we introduce a new vector space to represent word meaning based on words'' informational importance in the subject categories. Informational Space of Meaning for Scientific Texts a list of words where words are sorted in descending order by their RIGs can be created.

abstract:
  In Natural Language Processing, automatic extracting the meaning of texts constitutes an important problem. Our focus is the computational analysis of meaning of short scientific texts (abstracts or brief reports). In this paper, a vector space model is developed for quantifying the meaning of words and texts. We introduce the Meaning Space, in which the meaning of a word is represented by a vector of Relative Information Gain (RIG) about the subject categories that the text belongs to, which can be obtained from observing the word in the text. This new approach is applied to construct the Meaning Space based on Leicester Scientific Corpus (LSC) and Leicester Scientific Dictionary-Core (LScDC). The LSC is a scientific corpus of 1,673,350 abstracts and the LScDC is a scientific dictionary which words are extracted from the LSC. Each text in the LSC belongs to at least one of 252 subject categories of Web of Science (WoS). These categories are used in construction of vectors of information gains. The Meaning Space is described and statistically analysed for the LSC with the LScDC. The usefulness of the proposed representation model is evaluated through top-ranked words in each category. The most informative n words are ordered. We demonstrated that RIG-based word ranking is much more useful than ranking based on raw word frequency in determining the science-specific meaning and importance of a word. The proposed model based on RIG is shown to have ability to stand out topic-specific words in categories. The most informative words are presented for 252 categories. The new scientific dictionary and the 103,998 x 252 Word-Category RIG Matrix are available online. Analysis of the Meaning Space provides us with a tool to further explore quantifying the meaning of a text using more complex and context-dependent meaning models that use co-occurrence of words and their combinations.


id: cord-252485-cxi3cr15
author: Yoshida, Asuka
date: 2015-08-04
txt: ./txt/cord-252485-cxi3cr15.txt
cache: ./cache/cord-252485-cxi3cr15.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fmicb.2015.00804
doi: 10.3389/fmicb.2015.00804
summary:
  We and other groups have recently reported that recombinant viruses of Sendai virus (SeV), a prototype of the family Paramyxoviridae, in which the C proteins are knocked-out or mutated, generate dsRNA in infected cells at levels similar to the production of IFN-β (Takeuchi et al., 2008; Irie et al., 2010) . These unusual RNAs exhibited distinct properties in infected cells in terms of encapsidation with the viral N protein and subcellular distribution with SG marker proteins and RLRs. Our results suggest that RNA-typedependent mechanisms recognize and accumulate virus-derived, IFN-β-inducible, unusual RNAs into specific compartment to trigger the production of IFN-β, and that SeV may evade detection by the host innate immune system by preventing the production of these RNA species. Since the naked cbDI genomes have been reported readily to form an ideal structure as the RIG-I ligands of 5 -triphosphated, blunt-ended dsRNA (Kolakofsky, 1976) , these results indicated that the major IFN-β-inducing viral RNA species produced in the cells infected with CNT was encapsidated cbDI genomes, whereas those for SeV-4C(-) and NDV were not.

title:
  IFN-β-inducing, unusual viral RNA species produced by paramyxovirus infection accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner

abstract:
  The interferon (IFN) system is one of the most important defensive responses of mammals against viruses, and is rapidly evoked when the pathogen-associated molecular patterns (PAMPs) of viruses are sensed. Non-self, virus-derived RNA species have been identified as the PAMPs of RNA viruses. In the present study, we compared different types of IFN-β-inducing and -non-inducing viruses in the context of Sendai virus infection. We found that some types of unusual viral RNA species were produced by infections with IFN-β-inducing viruses and accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner. One of these structures was similar to the so-called antiviral stress granules (avSGs) formed by an infection with IFN-inducing viruses whose C proteins were knocked-out or mutated. Non-encapsidated, unusual viral RNA harboring the 5′-terminal region of the viral genome as well as RIG-I and typical SG markers accumulated in these granules. Another was a non-SG-like inclusion formed by an infection with the Cantell strain; a copyback-type DI genome, but not an authentic viral genome, specifically accumulated in the inclusion, whereas RIG-I and SG markers did not. The induction of IFN-β was closely associated with the production of these unusual RNAs as well as the formation of the cytoplasmic structures.


id: cord-254492-42d77vxf
title: Ubiquitin in the activation and attenuation of innate antiviral immunity
author: Heaton, Steven M.
date: 2016-01-11
txt: ./txt/cord-254492-42d77vxf.txt
cache: ./cache/cord-254492-42d77vxf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26712804/
doi: 10.1084/jem.20151531
summary:
  Here we review how hostand virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. Methods for this include substrate molecular mimicry, binding and blocking E3-substrate pairs, expressing virally encoded E3s/DUbs, and hijacking host E3s/DUbs. Additionally, a novel mechanism involving ubiquitin chain packaging into nascent virions for subsequent redeployment Viral infection activates danger signals that are transmitted via the retinoic acid-inducible gene 1-like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. Here we review how host-and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. RNF125 forms part of this process, ligating K48-linked polyubiquitin chains to the activated CARD of RIG-I and MDA5, leading to proteasome-mediated degradation of both receptors and diminished IFN-I signaling. MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors

abstract:
  Viral infection activates danger signals that are transmitted via the retinoic acid–inducible gene 1–like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression.


id: cord-254549-ev0oesu0
title: C-type lectin receptors and RIG-I-like receptors: new points on the oncogenomics map
author: Kutikhin, Anton G
date: 2012-02-24
txt: ./txt/cord-254549-ev0oesu0.txt
cache: ./cache/cord-254549-ev0oesu0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/22427730/
doi: 10.2147/cmar.s28983
summary:
  The fundamental basis for the association of the inherited coding variation in genes encoding C-type lectin receptors and RIG-I-like receptors with cancer is represented by the defects in the immune response (that are caused by various single nucleotide polymorphisms) against specific carcinogenic infectious agents. The issue of an association of single nucleotide polymorphisms of genes encoding C-type lectin receptors, RIG-I-like receptors, and proteins of pattern recognition receptor pathways with various features of cancer progression is open, and only further population studies would be likely to give a definite answer. Another interesting issue is that associations between single nucleotide polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk can be skewed by differences between cohorts in various immune responses and infections that may not influence cancer development.

abstract:
  The group of pattern recognition receptors includes families of Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors. They are key sensors for a number of infectious agents, some of which are oncogenic, and they launch an immune response against them, normally promoting their eradication. Inherited variations in genes encoding these receptors and proteins and their signaling pathways may affect their function, possibly modulating cancer risk and features of cancer progression. There are numerous studies investigating the association of single nucleotide polymorphisms within or near genes encoding Toll-like receptors and NOD-like receptors, cancer risk, and features of cancer progression. However, there is an almost total absence of articles analyzing the correlation between polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk or progression. Nevertheless, there is some evidence supporting the hypothesis that inherited C-type lectin receptor and RIG-I-like receptor variants can be associated with increased cancer risk. Certain C-type lectin receptors and RIG-I-like receptors recognize pathogen-associated molecular patterns of potentially oncogenic infectious agents, and certain polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors may have functional consequences at the molecular level that can lead to association of such single nucleotide polymorphisms with risk or progression of some diseases that may modulate cancer risk, so these gene polymorphisms may affect cancer risk indirectly. Polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors thereby may be correlated with a risk of lung, oral, esophageal, gastric, colorectal, and liver cancer, as well as nasopharyngeal carcinoma, glioblastoma, multiple myeloma, and lymphoma. The list of the most promising polymorphisms for oncogenomic investigations may include rs1926736, rs2478577, rs2437257, rs691005, rs2287886, rs735239, rs4804803, rs16910526, rs36055726, rs11795404, and rs10813831.


id: cord-254895-ym0jsir5
author: Eisenächer, Katharina
date: 2008-01-18
txt: ./txt/cord-254895-ym0jsir5.txt
cache: ./cache/cord-254895-ym0jsir5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18086372/
doi: 10.1016/j.imbio.2007.09.007
summary:
  Dendritic cell subpopulations express specific nucleic acid recognition receptors belonging to the Toll-like receptor family (TLR3, 7, 8, 9) and the cytosolic RNA helicase family (RIG-I, MDA5, LGP2). Apart from activating the NFkB and MAPK signaling pathways leading to inflammatory cytokine and chemokine production as well as costimulatory molecule expression, the intracellularly localized nucleic acid recognition receptors TLR3, 7, 8 and 9 specifically trigger type I interferon production via MyD88-and TRIF-dependent signaling pathways. Thus, TRAF6 seems to be required for NFkB activation but not IFN-b induction downstream of IPS-1 which is mainly mediated by TBK1/IKKe. In vitro studies performed with primary cells obtained from RIG-I knockout mice confirmed that RIG-I plays an essential role in eliciting immune responses against specific negative strand and positive strand RNA viruses such as NDV, SeV, VSV, Japanese encephalitis virus (JEV) and Influenza virus in various cell types with the exception of pDCs .

title:
  The role of viral nucleic acid recognition in dendritic cells for innate and adaptive antiviral immunity

abstract:
  Abstract Dendritic cells which are located at the interface of innate and adaptive immunity are targets for infection by many different DNA and RNA viruses. Dendritic cell subpopulations express specific nucleic acid recognition receptors belonging to the Toll-like receptor family (TLR3, 7, 8, 9) and the cytosolic RNA helicase family (RIG-I, MDA5, LGP2). Activation of dendritic cells by viral DNA and RNA via these receptors is essential for triggering the innate antiviral immune response and shaping the ensuing adaptive antiviral immunity. This review will summarize our current knowledge of viral nucleic acid recognition and signaling by Toll-like receptors and RNA helicases focusing on recent evidence for their specific functions in antiviral defense in vivo.


id: cord-257052-cik2wmlk
author: Ban, Junsu
date: 2018-12-14
txt: ./txt/cord-257052-cik2wmlk.txt
cache: ./cache/cord-257052-cik2wmlk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/v10120716
doi: 10.3390/v10120716
summary:
  title: Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling Collectively, this study suggests that RSV NS1 interacts with TRIM25 and interferes with RIG-I ubiquitination to suppress type-I interferon signaling. Ectopically expressed NS1 inhibited interferon-β promoter activity that was induced by RIG-IN as determined by the luciferase assays in HEK293T cells, confirming that NS1 itself is capable of inhibiting RIG-I-mediated antiviral signaling ( Figure 1A ). Ectopically expressed NS1 inhibited interferon-β promoter activity that was induced by RIG-IN as determined by the luciferase assays in HEK293T cells, confirming that NS1 itself is capable of inhibiting RIG-I-mediated antiviral signaling ( Figure 1A ). These results suggest that RSV NS1 expression diminishes the interaction between RIG-I and MAVS by interfering with TRIM25-mediated RIG-I ubiquitination. These results indicate that inhibition of TRIM25-mediated RIG-I ubiquitination by NS1 contributes to the suppression of RIG-I signaling, at least in part.

title:
  Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling

abstract:
  Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract disease. Retinoic acid-inducible gene-I (RIG-I) serves as an innate immune sensor and triggers antiviral responses upon recognizing viral infections including RSV. Since tripartite motif-containing protein 25 (TRIM25)-mediated K63-polyubiquitination is crucial for RIG-I activation, several viruses target initial RIG-I activation through ubiquitination. RSV NS1 and NS2 have been shown to interfere with RIG-I-mediated antiviral signaling. In this study, we explored the possibility that NS1 suppresses RIG-I-mediated antiviral signaling by targeting TRIM25. Ubiquitination of ectopically expressed RIG-I-2Cards domain was decreased by RSV infection, indicating that RSV possesses ability to inhibit TRIM25-mediated RIG-I ubiquitination. Similarly, ectopic expression of NS1 sufficiently suppressed TRIM25-mediated RIG-I ubiquitination. Furthermore, interaction between NS1 and TRIM25 was detected by a co-immunoprecipitation assay. Further biochemical assays showed that the SPRY domain of TRIM25, which is responsible for interaction with RIG-I, interacted sufficiently with NS1. Suppression of RIG-I ubiquitination by NS1 resulted in decreased interaction between RIG-I and its downstream molecule, MAVS. The suppressive effect of NS1 on RIG-I signaling could be abrogated by overexpression of TRIM25. Collectively, this study suggests that RSV NS1 interacts with TRIM25 and interferes with RIG-I ubiquitination to suppress type-I interferon signaling.


id: cord-257886-ytlnhyxr
author: Zhao, Kuan
date: 2019-05-03
txt: ./txt/cord-257886-ytlnhyxr.txt
cache: ./cache/cord-257886-ytlnhyxr.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.vetmic.2019.05.003
doi: 10.1016/j.vetmic.2019.05.003
summary:
  title: Nucleocapsid protein of porcine reproductive and respiratory syndrome virus antagonizes the antiviral activity of TRIM25 by interfering with TRIM25-mediated RIG-I ubiquitination These results indicate for the first time that TRIM25 inhibits PRRSV replication and that the N protein antagonizes the antiviral activity by interfering with TRIM25-mediated RIG-I ubiquitination. The cells were lysed in RIPA lysis buffer after 36 h of transfection and the effects of siRNAs were analyzed by WB using an anti-TRIM25 monoclonal antibody (cat. To investigate whether TRIM25-mediated RIG-I ubiquitination is regulated by the PRRSV N protein, HEK293T cells grown in 6-well plates were co-transfected with pCAGGS-Flag-RIG-I (0.5 μg per well) and HA-ubiquitin (0.5 μg per well), and the indicated amounts of the Myc-N expression plasmids. The experiment revealed that TRIM25-mediated RIG-I ubiquitination was potentiated by Sendai virus (SEV) infection but was substantially suppressed by increasing the PRRSV N protein expression, in a dose-dependent manner (Fig. 5) .

title:
  Nucleocapsid protein of porcine reproductive and respiratory syndrome virus antagonizes the antiviral activity of TRIM25 by interfering with TRIM25-mediated RIG-I ubiquitination

abstract:
  Porcine reproductive and respiratory syndrome (PRRS) is caused by PRRS virus (PRRSV), and is characterized by respiratory diseases in piglet and reproductive disorders in sow. Identification of sustainable and effective measures to mitigate PRRSV transmission is a pressing problem. The nucleocapsid (N) protein of PRRSV plays a crucial role in inhibiting host innate immunity during PRRSV infection. In the current study, a new host-restricted factor, tripartite motif protein 25 (TRIM25), was identified as an inhibitor of PRRSV replication. Co-immunoprecipitation assay indicated that the PRRSV N protein interferes with TRIM25–RIG-I interactions by competitively interacting with TRIM25. Furthermore, N protein inhibits the expression of TRIM25 and TRIM25-mediated RIG-I ubiquitination to suppress interferon β production. Furthermore, with increasing TRIM25 expression, the inhibitory effect of N protein on the ubiquitination of RIG-I diminished. These results indicate for the first time that TRIM25 inhibits PRRSV replication and that the N protein antagonizes the antiviral activity by interfering with TRIM25-mediated RIG-I ubiquitination. This not only provides a theoretical basis for the development of drugs to control PRRSV replication, but also better explains the mechanism through which the PRRSV N protein inhibits innate immune responses of the host.


id: cord-261532-q923xxn2
title: The essential adaptors of innate immune signaling
author: Chen, Huihui
date: 2012-09-21
txt: ./txt/cord-261532-q923xxn2.txt
cache: ./cache/cord-261532-q923xxn2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/22996173/
doi: 10.1007/s13238-012-2063-0
summary:
  Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors (PRRs) to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1, where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/ AP-1 and the signal transducer and activator of transcription 6 (STAT6) to trigger the expression of type I interferons and inflammatory cytokines or the assembly of inflammasomes. These receptors can recruit specific adaptor proteins, like myeloid differentiation primary response gene 88 (MyD88) or Toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing IFN-β (TRIF) in the TLR pathway, mitochondrial antiviral signaling protein (MAVS) downstream of RLRs, stimulator of interferon genes (STING) in the cytosolic DNA response pathway and, cysteine aspartic protease 1 (Caspase-1) as part of the inflammasome, all of which orchestrate the host innate responses, through activation of transcriptional factors such as nuclear factor κB (NF-κB), activator protein 1 (AP-1) and interferon regulatory factors (IRFs), to trigger the production of type І interferons (IFNs), inflammatory cytokines and chemokines.

abstract:
  Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors (PRRs) to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1, where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/ AP-1 and the signal transducer and activator of transcription 6 (STAT6) to trigger the expression of type I interferons and inflammatory cytokines or the assembly of inflammasomes. Most pleiotropic cytokines are secreted and bind to specific receptors, activating the signaling pathways including JAK-STAT for the proliferation, differentiation and functional capacity of immune cells. This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.


id: cord-268438-bjs5oliw
author: Jin, Yilin
date: 2019-12-03
txt: ./txt/cord-268438-bjs5oliw.txt
cache: ./cache/cord-268438-bjs5oliw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31849979/
doi: 10.3389/fimmu.2019.02805
summary:
  title: Zebrafish TRIM25 Promotes Innate Immune Response to RGNNV Infection by Targeting 2CARD and RD Regions of RIG-I for K63-Linked Ubiquitination Here, we found that zebrafish TRIM25 (zbTRIM25) functioned as a positive regulator of RLR signaling pathway during red spotted grouper nervous necrosis virus (RGNNV) infection. In the present study, zebrafish TRIM25 (zbTRIM25) was involved in RGNNV infection and was identified as a positive mediator of RLR signaling pathway by binding to and ubiquitinating the caspase activation and recruitment domain (2CARD) and repressor domain (RD) regions of RIG-I, which is different with the findings in mammals. In mammals, previous reports showed that TRIM25 enhanced RLRs antiviral pathway by binding viral RNA-activated RIG-I to induce its K63-linked polyubiquitination and subsequent IFNs and ISGs production (26) . Here, we found that zbTRIM25 positively regulated RLR signaling pathway and facilitated zbRIG-I-mediated IFN 1 promoter activation, and overexpression of zbTRIM25 inhibited RGNNV infection, indicating the conservative antiviral properties of TRIM25 in fish and mammals.

title:
  Zebrafish TRIM25 Promotes Innate Immune Response to RGNNV Infection by Targeting 2CARD and RD Regions of RIG-I for K63-Linked Ubiquitination

abstract:
  RIG-I-like receptors (RLRs) play important roles in response to virus infection by regulating host innate immune signaling pathways. Meanwhile, the RLR signaling pathway is also tightly regulated by host and virus to achieve the immune homeostasis between antiviral responses and virus survival. Here, we found that zebrafish TRIM25 (zbTRIM25) functioned as a positive regulator of RLR signaling pathway during red spotted grouper nervous necrosis virus (RGNNV) infection. Post-RGNNV infection, zbTRIM25 expression was obviously inhibited and ectopic expression of zbTRIM25 led to enhanced expression of RLR signaling pathway-related genes. Overexpression and knockdown analysis revealed that zbTRIM25 promoted zebrafish RIG-I (zbRIG-I)-mediated IFN signaling and inhibited RGNNV replication. Mechanistically, zbTRIM25 bound to zbRIG-I; in particular, the SPRY domain of zbTRIM25 interacted with the tandem caspase activation and recruitment domains (2CARD) and repressor domain (RD) regions of zbRIG-I. zbTRIM25 promoted the K63 polyubiquitination of 2CARD and RD regions of zbRIG-I. Furthermore, zbTRIM25-mediated zbRIG-I activation of IFN production was enhanced by K63-linked ubiquitin, indicating that zbTRIM25-mediated zbRIG-I polyubiquitination was essential for RIG-I-triggered IFN induction. In conclusion, these findings reveal a novel mechanism that zbTRIM25 positively regulates the innate immune response by targeting and promoting the K63-linked polyubiquitination of zbRIG-I.


id: cord-278523-djjtgbh6
author: Zhou, Bei-xian
date: 2020-06-05
txt: ./txt/cord-278523-djjtgbh6.txt
cache: ./cache/cord-278523-djjtgbh6.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41401-020-0403-9
doi: 10.1038/s41401-020-0403-9
summary:
  We demonstrate that β-sitosterol (150–450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Together, these data demonstrate that β-sitosterol blocks the IAV-induced amplification of the proinflammatory response in IFN-β-activated A549 cells, which is due to inhibition of RIG-I levels by β-sitosterol, leading to the inactivation of STAT1, and thereby diminishes the transcriptional activity of interferon-stimulated gene factor 3 (ISGF3).

title:
  β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling

abstract:
  β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity. In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that β-sitosterol (150–450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Moreover, β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors. In a mouse model of influenza, pre-administration of β-sitosterol (50, 200 mg·kg(−1)·d(−1), i.g., for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation. In addition, pre-administration of β-sitosterol protected mice from lethal IAV infection. Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.


id: cord-283096-qm7h4qui
title: ISG15 and immune diseases
author: Jeon, Young Joo
date: 2010-02-12
txt: ./txt/cord-283096-qm7h4qui.txt
cache: ./cache/cord-283096-qm7h4qui.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/20153823/
doi: 10.1016/j.bbadis.2010.02.006
summary:
  Some of them are type I IFN-induced proteins, such as PKR and RIG-I, and some are the key regulators that are involved in IFN signaling, such as JAK1 and STAT1, implicating the role of ISG15 and its conjugates in type I IFN-mediated innate immune responses. Viral infection also strongly induces ISG15 [18, 19] because one of its major host responses is the production of type I IFNs. A number of proteins that are involved in antiviral signaling pathways, including RIG-I, MDA-5, Mx1, PKR, STAT1, and JAK1, have been identified as target proteins for ISGylation. Swiss 3T3 cells expressing constitutively active MKK7-JNK1β fusion protein show increased resistance to apoptosis induced by vesicular stomatitis virus (VSV) infection, suggesting the involvement of JNK signaling pathway in antiviral response. acid seems to elevate the levels of ISG15 and its conjugates by stimulating cells to secrete IFNs. UBE1L is a 112-kDa protein that shows a 45% identity in amino acid sequence to the human ubiquitin-activating E1 enzyme (UBE1) [73] .

abstract:
  ISG15, the product of interferon (IFN)-stimulated gene 15, is the first identified ubiquitin-like protein, consisting of two ubiquitin-like domains. ISG15 is synthesized as a precursor in certain mammals and, therefore, needs to be processed to expose the C-terminal glycine residue before conjugation to target proteins. A set of three-step cascade enzymes, an E1 enzyme (UBE1L), an E2 enzyme (UbcH8), and one of several E3 ligases (e.g., EFP and HERC5), catalyzes ISG15 conjugation (ISGylation) of a specific protein. These enzymes are unique among the cascade enzymes for ubiquitin and other ubiquitin-like proteins in that all of them are induced by type I IFNs or other stimuli, such as exposure to viruses and lipopolysaccharide. Mass spectrometric analysis has led to the identification of several hundreds of candidate proteins that can be conjugated by ISG15. Some of them are type I IFN-induced proteins, such as PKR and RIG-I, and some are the key regulators that are involved in IFN signaling, such as JAK1 and STAT1, implicating the role of ISG15 and its conjugates in type I IFN-mediated innate immune responses. However, relatively little is known about the functional significance of ISG15 induction due to the lack of information on the consequences of its conjugation to target proteins. Here, we describe the recent progress made in exploring the biological function of ISG15 and its reversible modification of target proteins and thus in their implication in immune diseases.


id: cord-284156-btb4oodz
title: Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity
author: Liu, Yiliu
date: 2017-01-03
txt: ./txt/cord-284156-btb4oodz.txt
cache: ./cache/cord-284156-btb4oodz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28096803/
doi: 10.3389/fimmu.2016.00662
summary:
  Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. They function as cytoplasmic sensors for the recognition of a variety of RNA viruses and subsequent activation of downstream signaling to drive type I IFN production and antiviral gene expressions. (c) Interactions between RIG-I-TRIM25 complex and 14-3-3ϵ promote RIG-I translocation to mitochondrial mitochondrial antiviral signaling protein (MAVS) for downstream signaling, leading to interferon production. Protein purification and mass spectrometry analysis identified that phosphorylation of Thr170 in the CARDs antagonizes RIG-I signaling by inhibiting TRIM25-mediated Lys172 ubiquitination and MAVS binding (68) . Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response

abstract:
  Innate immunity is the first line of defense against invading pathogens. Rapid and efficient detection of pathogen-associated molecular patterns via pattern-recognition receptors is essential for the host to mount defensive and protective responses. Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. Upon viral RNA recognition, RIG-I recruits the mitochondrial adaptor protein mitochondrial antiviral signaling protein, which leads to a signaling cascade that coordinates the induction of type I interferons (IFNs), as well as a large variety of antiviral interferon-stimulated genes. The RIG-I activation is tightly regulated via various posttranslational modifications for the prevention of aberrant innate immune signaling. By contrast, viruses have evolved mechanisms of evasion, such as sequestrating viral structures from RIG-I detections and targeting receptor or signaling molecules for degradation. These virus–host interactions have broadened our understanding of viral pathogenesis and provided insights into the function of the RIG-I pathway. In this review, we summarize the recent advances regarding RIG-I pathogen recognition and signaling transduction, cell-intrinsic control of RIG-I activation, and the viral antagonism of RIG-I signaling.


id: cord-285339-pwy1ry4n
author: Tarigan, Ronald
date: 2020-06-18
txt: ./txt/cord-285339-pwy1ry4n.txt
cache: ./cache/cord-285339-pwy1ry4n.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0006291X20307865
doi: 10.1016/j.bbrc.2020.04.060
summary:
  Here, kidney epithelial cell lines derived from four bat species (Pteropus dasymallus, Rousettus leschenaultii, Rhinolophus ferrumequinum, and Miniopterus fuliginosus) and two non-bat species (Homo sapiens and Mesocricetus auratus) were infected with EMCV and JEV. fuliginosus with a higher expression level of pattern recognition receptors (PRRs) (TLR3, RIG-I, and MDA5) and interferon-beta (IFN-β) than that in the non-bat cell lines and a bat cell line derived from P. The knockdown of TLR3, RIG-I, and MDA5 in Rhinolophus bat cell line using antisense RNA oligonucleotide led to decrease IFN-β expression and increased viral replication. EMCV and JEV infection resulted in a higher expression level of PRRs in bat cell lines with a lower viral replication level (DEMKT1, BKT1, and YUBFKT1) (Fig. 2B, C, and 2D ).

title:
  Role of pattern recognition receptors and interferon-beta in protecting bat cell lines from encephalomyocarditis virus and Japanese encephalitis virus infection

abstract:
  Bats are potential natural hosts of Encephalomyocarditis virus (EMCV) and Japanese encephalitis virus (JEV). Bats appear to have some unique features in their innate immune system that inhibit viral replication causing limited clinical symptoms, and thus, contributing to the virus spill over to humans. Here, kidney epithelial cell lines derived from four bat species (Pteropus dasymallus, Rousettus leschenaultii, Rhinolophus ferrumequinum, and Miniopterus fuliginosus) and two non-bat species (Homo sapiens and Mesocricetus auratus) were infected with EMCV and JEV. The replication of EMCV and JEV was lower in the bat cell lines derived from R. leschenaultii, R. ferrumequinum, and M. fuliginosus with a higher expression level of pattern recognition receptors (PRRs) (TLR3, RIG-I, and MDA5) and interferon-beta (IFN-β) than that in the non-bat cell lines and a bat cell line derived from P. dasymallus. The knockdown of TLR3, RIG-I, and MDA5 in Rhinolophus bat cell line using antisense RNA oligonucleotide led to decrease IFN-β expression and increased viral replication. These results suggest that TLR3, RIG-I, and MDA5 are important for antiviral response against EMCV and JEV in Rhinolophus bats.


id: cord-287855-jfrg9soy
title: Influenza virus and cell signaling pathways
author: Gaur, Pratibha
date: 2011-06-01
txt: ./txt/cord-287855-jfrg9soy.txt
cache: ./cache/cord-287855-jfrg9soy.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/21629204/
doi: 10.12659/msm.881801
summary:
  During viral infection there is activation of the NF-kB signaling pathway and an increase in the gene expression levels of IFN-b/TNFa/IL8 [22, 23] , which suggests that IKK-mediated NF-kB signaling is essential for the host innate immune response [24] . Activation of Akt through phosphorylation at Thr 308 and Ser 473 residues [42] plays a major role in modulating diverse downstream signaling pathways, including cell survival, proliferation, migration, differentiation and inhibition of proapoptotic factors such as BAD and caspase-9 by their phosphorylation (Figure 1(1) ). Mitogen activated protein kinase (MAPK) cascades are involved in the conversion of various extracellular signals into cellular responses as diverse as proliferation, differentiation, immune response and cell death [51, 52] . Binding of influenza virus HA protein to host cell surface receptor activates PKC [12, 77, 78] , and overexpression of HA inside the cells induces ERK signaling. Most importantly, NS1 protein reduces the antiviral response by activating NF-kB signaling and also activates PI3K/Akt pathway for efficient viral replication.

abstract:
  Influenza viruses comprise a major class of human respiratory pathogens, responsible for causing morbidity and mortality worldwide. Influenza A virus, due to its segmented RNA genome, is highly subject to mutation, resulting in rapid formation of variants. During influenza infection, viral proteins interact with host proteins and exploit a variety of cellular pathways for their own benefit. Influenza virus inhibits the synthesis of these cellular proteins and facilitates expression of its own proteins for viral transcription and replication. Infected cell pathways are hijacked by an array of intracellular signaling cascades such as NF-κB signaling, PI3K/Akt pathway, MAPK pathway, PKC/PKR signaling and TLR/RIG-I signaling cascades. This review presents a research update on the subject and discusses the impact of influenza viral infection on these cell signaling pathways.


id: cord-288390-p1q3v1ie
title: Cytoplasmic sensing of viral nucleic acids
author: Habjan, Matthias
date: 2015-02-07
txt: ./txt/cord-288390-p1q3v1ie.txt
cache: ./cache/cord-288390-p1q3v1ie.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S1879625715000140
doi: 10.1016/j.coviro.2015.01.012
summary:
  These sensors induce expression of cytokines, affect cellular functions required for virus replication and directly target viral nucleic acids through degradation or sequestration. These sensors induce expression of cytokines, affect cellular functions required for virus replication and directly target viral nucleic acids through degradation or sequestration. In this review we concentrate on intracellular nucleic acid sensors and effector proteins that evolved to mediate specialised tasks including, firstly, expression of cytokines such as type I interferons (IFN-a/b); secondly, modulation of cellular machineries required for virus replication and thirdly, direct inhibition of virus growth ( Figure 1 ). Among the best characterised cytoplasmic proteins involved in virus sensing are RIG-I-like receptors (RLRs), a family of DExD/H-box helicases which specifically identify viral RNAs and have the ability to stimulate expression of IFN-a/b and other cytokines (Figure 3 ) [4, 17] . Virus infection activates a restricted set of sensor and effector proteins that modulate cellular pathways and directly target viral nucleic acid, thereby shaping the innate immune response.

abstract:
  Viruses are the most abundant pathogens on earth. A fine-tuned framework of intervening pathways is in place in mammalian cells to orchestrate the cellular defence against these pathogens. Key for this system is sensor proteins that recognise specific features associated with nucleic acids of incoming viruses. Here we review the current knowledge on cytoplasmic sensors for viral nucleic acids. These sensors induce expression of cytokines, affect cellular functions required for virus replication and directly target viral nucleic acids through degradation or sequestration. Their ability to respond to a given nucleic acid is based on both the differential specificity of the individual proteins and the downstream signalling or adaptor proteins. The cooperation of these multiple proteins and pathways plays a key role in inducing successful immunity against virus infections.


id: cord-299754-tgexahwd
title: The TRIMendous Role of TRIMs in Virus–Host Interactions
author: van Tol, Sarah
date: 2017-08-22
txt: ./txt/cord-299754-tgexahwd.txt
cache: ./cache/cord-299754-tgexahwd.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28829373/
doi: 10.3390/vaccines5030023
summary:
  Downstream of the initial pattern recognition, TRIMs also influence the recruitment and interaction of adaptor molecules (stimulator of IFN genes (STING), mitochondrial antiviral signaling protein (MAVS), TGF-β-activated kinase 1(TAK1)/MAP3K7-binding protein (TAB) 2, Myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapterinducing interferon-β (TRIF), NF-κB essential modulator (NEMO), nucleosome assembly protein (NAP-1), and tumor necrosis factor (TNF) receptor-associated factors (TRAF) family memberassociated NF-κB activator (TANK)) and enzymes (TRAF3, TRAF6, TAK1, inhibitor of NF-κB (IκB) kinase (IKK) α,β,ε, TANK binding kinase 1 (TBK1)) to signaling complexes in order to activate transcription factors. Downstream of the initial pattern recognition, TRIMs also influence the recruitment and interaction of adaptor molecules (stimulator of IFN genes (STING), mitochondrial antiviral signaling protein (MAVS), TGF-β-activated kinase 1(TAK1)/MAP3K7-binding protein (TAB) 2, Myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), NF-κB essential modulator (NEMO), nucleosome assembly protein (NAP-1), and tumor necrosis factor (TNF) receptor-associated factors (TRAF) family member-associated NF-κB activator (TANK)) and enzymes (TRAF3, TRAF6, TAK1, inhibitor of NF-κB (IκB) kinase (IKK) α,β,ε, TANK binding kinase 1 (TBK1)) to signaling complexes in order to activate transcription factors.

abstract:
  The innate antiviral response is integral in protecting the host against virus infection. Many proteins regulate these signaling pathways including ubiquitin enzymes. The ubiquitin-activating (E1), -conjugating (E2), and -ligating (E3) enzymes work together to link ubiquitin, a small protein, onto other ubiquitin molecules or target proteins to mediate various effector functions. The tripartite motif (TRIM) protein family is a group of E3 ligases implicated in the regulation of a variety of cellular functions including cell cycle progression, autophagy, and innate immunity. Many antiviral signaling pathways, including type-I interferon and NF-κB, are TRIM-regulated, thus influencing the course of infection. Additionally, several TRIMs directly restrict viral replication either through proteasome-mediated degradation of viral proteins or by interfering with different steps of the viral replication cycle. In addition, new studies suggest that TRIMs can exert their effector functions via the synthesis of unconventional polyubiquitin chains, including unanchored (non-covalently attached) polyubiquitin chains. TRIM-conferred viral inhibition has selected for viruses that encode direct and indirect TRIM antagonists. Furthermore, new evidence suggests that the same antagonists encoded by viruses may hijack TRIM proteins to directly promote virus replication. Here, we describe numerous virus–TRIM interactions and novel roles of TRIMs during virus infections.


id: cord-299964-sn5o3ugb
author: Xue, Qiao
date: 2018-11-05
txt: ./txt/cord-299964-sn5o3ugb.txt
cache: ./cache/cord-299964-sn5o3ugb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30408499/
doi: 10.1016/j.antiviral.2018.10.028
summary:
  Furthermore, 3C(pro) inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-β and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3C(pro) abrogated its deubiquitinating activity and the ability of 3C(pro) to block IFN-β induction. To determine whether SVV can evade innate immune response by inhibiting the host ubiquitination, HEK293T cells were transfected with FLAG-tagged VP1, VP2, 2AB, 2B, 2C, 3D, 3C plasmids along with HA-Ub plasmid. As shown in Fig. 1A , expression of 3C pro resulted in a dose-dependent reduction of the level of ubiquitinated cellular proteins compared with that in the empty vector-transfected cells. Taken together, these results indicate that SVV and 3C pro inhibit the ubiquitination of RIG-I, TBK1, and TRAF3 in a DUB-dependent manner.

title:
  Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

abstract:
  The mechanisms that enable Seneca Valley Virus (SVV) to escape the host innate immune response are not well known. Previous studies demonstrated that SVV 3C(pro) suppresses innate immune responses by cleavage of host proteins and degradation of IRF3 and IRF7 protein expression. Here, we showed that SVV 3C protease (3C(pro)) has deubiquitinating activity. Overexpressed 3C(pro) inhibits the ubiquitination of cellular substrates, acting on both lysine-48- and lysine-63-linked polyubiquitin chains. SVV infection also possessed deubiquitinating activity. The ubiquitin-proteasome system was significantly involved in SVV replication. Furthermore, 3C(pro) inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-β and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3C(pro) abrogated its deubiquitinating activity and the ability of 3C(pro) to block IFN-β induction. Together, our results demonstrate a novel mechanism developed by SVV 3C(pro) to promote viral replication, and may also provide a novel strategy for improving ubiquitination-based therapy.


id: cord-301362-f3lp10lm
author: Delgui, Laura R.
date: 2017-01-20
txt: ./txt/cord-301362-f3lp10lm.txt
cache: ./cache/cord-301362-f3lp10lm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28164038/
doi: 10.3389/fcimb.2017.00005
summary:
  Recognition of viral double-strand RNA (dsRNA) molecules by intracellular Toll-like receptors (TLRs) or retinoic acid inducible gene I-like receptors (RLRs) is a central event which entails the early steps of the immune response elicited during viral infections. Despite several differences among host range, viral structure, genome organization or membrane-donor organelles from the cell, these analyses revealed that +sRNA viruses are able to induce two types of membranous modifications as replicative niches: invaginated vesicles or spherules or a double membrane vesicle type. Endogenous RNAs forming secondary double-stranded structures that are released after necrosis and tissue damage after viral infection represent another source of dsRNA molecules reaching the endosomes, inducing host-derived dsRNA-mediated inflammatory responses through TLR-3 recognition (Kawai and Akira, 2010) . Other +sRNA viruses such as the enterovirus Coxsackievirus (Kemball et al., 2010) , Hepatitis C virus (Flaviviridae family) (Sir et al., 2012) , or Coronavirus such as MVH (Reggiori et al., 2010) also usurp the autophagy pathway and induce remarkably alterations in intracellular membranous components to harbor the sites for viral RNA replication.

title:
  A Novel Mechanism Underlying the Innate Immune Response Induction upon Viral-Dependent Replication of Host Cell mRNA: A Mistake of +sRNA Viruses'' Replicases

abstract:
  Viruses are lifeless particles designed for setting virus-host interactome assuring a new generation of virions for dissemination. This interactome generates a pressure on host organisms evolving mechanisms to neutralize viral infection, which places the pressure back onto virus, a process known as virus-host cell co-evolution. Positive-single stranded RNA (+sRNA) viruses are an important group of viral agents illustrating this interesting phenomenon. During replication, their genomic +sRNA is employed as template for translation of viral proteins; among them the RNA-dependent RNA polymerase (RdRp) is responsible of viral genome replication originating double-strand RNA molecules (dsRNA) as intermediates, which accumulate representing a potent threat for cellular dsRNA receptors to initiate an antiviral response. A common feature shared by these viruses is their ability to rearrange cellular membranes to serve as platforms for genome replication and assembly of new virions, supporting replication efficiency increase by concentrating critical factors and protecting the viral genome from host anti-viral systems. This review summarizes current knowledge regarding cellular dsRNA receptors and describes prototype viruses developing replication niches inside rearranged membranes. However, for several viral agents it's been observed both, a complex rearrangement of cellular membranes and a strong innate immune antiviral response induction. So, we have included recent data explaining the mechanism by, even though viruses have evolved elegant hideouts, host cells are still able to develop dsRNA receptors-dependent antiviral response.


id: cord-303189-ktl4jw8v
title: Early IFN type I response: Learning from microbial evasion strategies
author: Coccia, Eliana M.
date: 2015-03-31
txt: ./txt/cord-303189-ktl4jw8v.txt
cache: ./cache/cord-303189-ktl4jw8v.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.smim.2015.03.005
doi: 10.1016/j.smim.2015.03.005
summary:
  Acting in both autocrine and paracrine manner, IFN interferes with viral replication by inducing hundreds of different IFN-stimulated genes with both direct anti-pathogenic as well as immunomodulatory activities, therefore functioning as a bridge between innate and adaptive immunity. In these cells, the HCV-induced miR-21 has been recently reported to be involved in evasion of IFN-I production and stimulation of HCV replication, upon suppression of MyD88 and IRAK1 expression, that is required for the TLR7-mediated sensing of the virus [100] . Amongst RNA viruses that, as HCV, can establish a persistent infection, HIV-1, a lentivirus from the Retroviridae family, represents a paradigm for its ability to prevent or circumvent the innate immune response mediated by IFN-I. Overall, viruses as HCV and HIV-1 have evolved nifty strategies to dampen the host innate response in cells where a productive infection may take place, while they induce infection-independent mechanisms in non-permissive cells to facilitate the viral life cycle and promote a chronic inflammation.

abstract:
  Abstract Type I interferon (IFN) comprises a class of cytokines first discovered more than 50 years ago and initially characterized for their ability to interfere with viral replication and restrict locally viral propagation. As such, their induction downstream of germ-line encoded pattern recognition receptors (PRRs) upon recognition of pathogen-associated molecular patterns (PAMPs) is a hallmark of the host antiviral response. The acknowledgment that several PAMPs, not just of viral origin, may induce IFN, pinpoints at these molecules as a first line of host defense against a number of invading pathogens. Acting in both autocrine and paracrine manner, IFN interferes with viral replication by inducing hundreds of different IFN-stimulated genes with both direct anti-pathogenic as well as immunomodulatory activities, therefore functioning as a bridge between innate and adaptive immunity. On the other hand an inverse interference to escape the IFN system is largely exploited by pathogens through a number of tactics and tricks aimed at evading, inhibiting or manipulating the IFN pathway, that result in progression of infection or establishment of chronic disease. In this review we discuss the interplay between the IFN system and some selected clinically important and challenging viruses and bacteria, highlighting the wide array of pathogen-triggered molecular mechanisms involved in evasion strategies.


id: cord-305737-bnzd7b25
title: Targeting the viral Achilles’ heel: recognition of 5′-triphosphate RNA in innate anti-viral defence
author: Rehwinkel, Jan
date: 2013-05-23
txt: ./txt/cord-305737-bnzd7b25.txt
cache: ./cache/cord-305737-bnzd7b25.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.mib.2013.04.009
doi: 10.1016/j.mib.2013.04.009
summary:
  Targeting the viral Achilles'' heel: recognition of 5 0 -triphosphate RNA in innate anti-viral defence Jan Rehwinkel 1 and Caetano Reis e Sousa 2 Some RNA virus genomes bear 5 0 -triphosphates, which can be recognized in the cytoplasm of infected cells by host proteins that mediate anti-viral immunity. Both the innate sensor RIG-I and the interferon-induced IFIT proteins bind to 5 0 -triphosphate viral RNAs. RIG-I signals for induction of interferons during RNA virus infection while IFITs sequester viral RNAs to exert an antiviral effect. Recent work shows that the IFN system targets 5PPP RNAs during both phases: both RIG-I, a virus sensor that induces IFN expression, and IFITs, effector molecules that execute anti-viral activities, can specifically recognize 5PPP RNAs. As such, 5PPP RNAs appear to be Achilles'' heel of many RNA viruses in their interaction with the innate immune system (Figure 3a ).

abstract:
  Some RNA virus genomes bear 5′-triphosphates, which can be recognized in the cytoplasm of infected cells by host proteins that mediate anti-viral immunity. Both the innate sensor RIG-I and the interferon-induced IFIT proteins bind to 5′-triphosphate viral RNAs. RIG-I signals for induction of interferons during RNA virus infection while IFITs sequester viral RNAs to exert an anti-viral effect. Notably, the structures of these proteins reveal both similarities and differences, which are suggestive of independent evolution towards ligand binding. 5′-triphosphates, which are absent from most RNAs in the cytosol of uninfected cells, are thus a marker of virus infection that is targeted by the innate immune system for both induction and execution of the anti-viral response.


id: cord-306533-lvm11o4r
title: Regulatory interplay between deubiquitinating enzymes and cytokines
author: Woo, Bean
date: 2019-06-08
txt: ./txt/cord-306533-lvm11o4r.txt
cache: ./cache/cord-306533-lvm11o4r.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31208841/
doi: 10.1016/j.cytogfr.2019.06.001
summary:
  DUBs interact with some of the key molecules in the IFN signaling pathway, which include, but are not limited to, RIG-I, stimulator of interferon genes (STING), tumor necrosis factor receptor-associated factors (TRAFs), interferon regulatory factor are summarized in Table 1 . A study conducted using human kidney mesangial cells (MC) showed slightly different results: silencing CYLD in MC cells and stimulating them with poly IC increased the toll-like receptor 3 (TLR3)-induced activation of RIG-I and MDA5 [26] ; however, the level of mRNA of RIG-I and MDA5 actually decreased [26] . However, when USP18 -/-MEF cells with either WT USP18 or DUB activity-mutated USP18 were induced with HSV-1, HCMV or cytosolic DNA, Ifnb, Ifna4, Tnf, IL-6 or Cxcl1 genes increased in expression, indicating that the deubiquitinating activity of USP18 is not responsible for this phenomenon [41] . In a study by Malakhova et al., USP18 inhibited IFN-induced gene activation by affecting JAK-STAT signaling pathway in 293 T cells [44] .

abstract:
  Deubiquitinating enzymes (DUBs) are cysteine protease proteins that reverse the ubiquitination by removing ubiquitins from the target protein. With over 100 DUBs identified and categorized into at least 7 families, many DUBs interact with one or more cytokines, influencing cellular processes, such as antiviral responses, inflammatory responses, apoptosis, etc. While some DUBs influence cytokine pathway or production, some DUBs are cytokine-inducible. In this article, we summarize a list of DUBs, their interaction with cytokines, target proteins and mechanisms of action.


id: cord-307598-p54p7enk
title: Master sensors of pathogenic RNA – RIG-I like receptors
author: Schlee, Martin
date: 2013-07-01
txt: ./txt/cord-307598-p54p7enk.txt
cache: ./cache/cord-307598-p54p7enk.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0171298513001204
doi: 10.1016/j.imbio.2013.06.007
summary:
  Similar to TLRs, RIG-I and MDA5 induce type I IFN and chemokines (but no IL12) upon activation by viral but also bacterial RNA. Since type I IFN induction by this RNA required RNase L, the authors concluded that RNase L recognizes and processes viral mRNA into a MDA5 activating structure. Before 5 triphosphate was identified as the crucial RNA modification to induce RIG-I activation, Marques and colleagues observed that synthetic blunt ended dsRNA oligonucleotides can stimulate RIG-I ( Fig. 3 ) (Marques et al. (2010b) confirmed the requirement of a base paired 5 -ppp end of dsRNA for RIG-I activation and suggested that some arenaviruses and bunyaviruses use a prime and realign mechanism for genome synthesis, leading to 5 overhangs in order to evade RIG-I recognition (Marq et al. pneumophilae did not induce type I IFN in HEK293 cells, thus excluding RIG-I-mediated recognition of RNA polymerase-III transcripts in the host cell, as previously suggested (Chiu et al.

abstract:
  Initiating the immune response to invading pathogens, the innate immune system is constituted of immune receptors (pattern recognition receptors, PRR) that sense microbe-associated molecular patterns (MAMPs). Detection of pathogens triggers intracellular defense mechanisms, such as the secretion of cytokines or chemokines to alarm neighboring cells and attract or activate immune cells. The innate immune response to viruses is mostly based on PRRs that detect the unusual structure, modification or location of viral nucleic acids. Most of the highly pathogenic and emerging viruses are RNA genome-based viruses, which can give rise to zoonotic and epidemic diseases or cause viral hemorrhagic fever. As viral RNA is located in the same compartment as host RNA, PRRs in the cytosol have to discriminate between viral and endogenous RNA by virtue of their structure or modification. This challenging task is taken on by the homologous cytosolic DExD/H-box family helicases RIG-I and MDA5, which control the innate immune response to most RNA viruses. This review focuses on the molecular basis for RIG-I like receptor (RLR) activation by synthetic and natural ligands and will discuss controversial ligand definitions.


id: cord-307914-lgprrwee
title: Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids
author: Bartok, Eva
date: 2020-07-14
txt: ./txt/cord-307914-lgprrwee.txt
cache: ./cache/cord-307914-lgprrwee.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.immuni.2020.06.014
doi: 10.1016/j.immuni.2020.06.014
summary:
  Indeed, the functionalization of CRISPR/Cas systems as a tool for genomic editing have revealed important differences in human and murine NA sensing, including distinct cell subset expression patterns of NA-sensing Toll-Like Receptors (TLRs) or species differences in the structural requirements for the detection of cyclic dinucleotide cGAMP by STING. As a long dsRNA with a 5 0 diphosphate terminus, polyI:C is known to activate the sensing receptors TLR3, MDA5, and RIG-I (Alexopoulou et al., 2001; Gitlin et al., 2006; Kato et al., 2008; Yoneyama et al., 2005) , accessory proteins such including LGP2 and members of the DDX and DHX families (reviewed in Oshiumi et al., 2016) as well as the restriction factors PKR and the OAS family (Farrell et al., 1978; Hovanessian et al., 1977; Zilberstein et al., 1978) .

abstract:
  All lifeforms have developed highly sophisticated systems equipped to detect altered self and non-self nucleic acids (NA). In vertebrates, NA-sensing receptors safeguard the integrity of the organism by detecting pathogens, dyshomeostasis and damage, and inducing appropriate responses to eliminate pathogens and reconstitute homeostasis. Effector mechanisms include i) immune signaling, ii) restriction of NA functions such as inhibition of mRNA translation, and iii) cell death pathways. An appropriate effector response is necessary for host defense, but dysregulated NA-sensing can lead to devastating autoimmune and autoinflammatory disease. Their inherent biochemical similarity renders the reliable distinction between self NA under homeostatic conditions and altered or exogenous NA particularly challenging. In this review, we provide an overview of recent progress in our understanding of the closely coordinated and regulated network of innate immune receptors, restriction factors, and nucleases to effectively respond to pathogens and maintain host integrity.


id: cord-311823-85wj08gr
title: Innate immune modulation by RNA viruses: emerging insights from functional genomics
author: Katze, Michael G.
date: 2008
txt: ./txt/cord-311823-85wj08gr.txt
cache: ./cache/cord-311823-85wj08gr.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/nri2377
doi: 10.1038/nri2377
summary:
  In this section, we review recent studies in which genomic approaches have been used to provide new information on how viruses trigger and regulate innate immune pathways, and to evaluate the use of type I IFN-based therapy as a means to enhance the innate immune response to HCV. In RIg-I-deficient cells, influenza virus fails to elicit the expression of IFNβ and of many ISgs, including key antiviral mediators such as IRF3, STAT1 (signal transducer and activator of transcription 1), IFIT1 (IFN-induced protein with tetratricopeptide repeats 1; also known as ISg56) and ISg54 (also known as IFIT2). Although these studies have provided considerable information regarding the genes activated downstream of TlR activation, it will be advantageous to extend genomic analyses in the context of viral infection using cells lacking the expression of specific TlRs. The ability of a virus to establish an infection depends, at least to some extent, on its ability to block the host innate immune response or to modulate the activity of antiviral effector proteins.

abstract:
  Although often encoding fewer than a dozen genes, RNA viruses can overcome host antiviral responses and wreak havoc on the cells they infect. Some manage to evade host antiviral defences, whereas others elicit an aberrant or disproportional immune response. Both scenarios can result in the disruption of intracellular signalling pathways and significant pathology in the host. Systems-biology approaches are increasingly being used to study the processes of viral triggering and regulation of host immune responses. By providing a global and integrated view of cellular events, these approaches are beginning to unravel some of the complexities of virus–host interactions and provide new insights into how RNA viruses cause disease.


id: cord-312001-8p7scli8
title: The Innate Antiviral Response in Animals: An Evolutionary Perspective from Flagellates to Humans
author: Majzoub, Karim
date: 2019-08-16
txt: ./txt/cord-312001-8p7scli8.txt
cache: ./cache/cord-312001-8p7scli8.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/v11080758
doi: 10.3390/v11080758
summary:
  Consequently, animal cells have evolved devoted pathways which (1) sense and recognize pathogen-associated molecular patterns (PAMPs) and, more particularly, virus-associated molecular signatures; (2) initiate signaling cascades stemming from the site of detection, translocating the information to the nucleus; and (3) induce a transcriptional program that confers an antiviral state to the host ( Figure 1 ). While the cytosolic recognition of viral RNA is almost exclusively mediated by RLRs, several proteins have been proposed to play a role in DNA sensing and triggering innate immune responses, such as the DNA-dependent activator of IFN-regulatory factors (DAI), DDX41, RNA polymerase III, IFI16 and DNA-PK [62] [63] [64] [65] [66] [67] . Although the pathway leading to the transcriptional activation of Vago is still poorly understood in insects, these studies established that DExD/H-box helicase containing proteins, like Dicer and RLRs, may represent an evolutionarily conserved set of viral nucleic acid sensors that direct antiviral responses in animals [159] .

abstract:
  Animal cells have evolved dedicated molecular systems for sensing and delivering a coordinated response to viral threats. Our understanding of these pathways is almost entirely defined by studies in humans or model organisms like mice, fruit flies and worms. However, new genomic and functional data from organisms such as sponges, anemones and mollusks are helping redefine our understanding of these immune systems and their evolution. In this review, we will discuss our current knowledge of the innate immune pathways involved in sensing, signaling and inducing genes to counter viral infections in vertebrate animals. We will then focus on some central conserved players of this response including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and cGAS-STING, attempting to put their evolution into perspective. To conclude, we will reflect on the arms race that exists between viruses and their animal hosts, illustrated by the dynamic evolution and diversification of innate immune pathways. These concepts are not only important to understand virus-host interactions in general but may also be relevant for the development of novel curative approaches against human disease.


id: cord-312075-asbt0mcj
title: Viral Evasion Strategies in Type I IFN Signaling – A Summary of Recent Developments
author: Schulz, Katharina S.
date: 2016-11-11
txt: ./txt/cord-312075-asbt0mcj.txt
cache: ./cache/cord-312075-asbt0mcj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/27891131/
doi: 10.3389/fimmu.2016.00498
summary:
  Human T-cell lymphotropic virus type I (HTLV-1) protein Tax disrupts innate immune signaling in multiple ways: it binds to the RIP homotypic interaction motif (RHIM) domains of RIP-1 and disrupts the interaction between RIP-1 and RIG-I or MDA-5 and the activation of the type I IFN promoter. Upon stimulation, TBK1 and IKKε are recruited by adaptor proteins to signaling complexes to be activated by phosphorylation on Ser172 and both have been shown to be subjected to K63-linked polyubiquitination [reviewed in Ref. Interestingly, when a recent study tested how the rabies virus P protein of street strains behaves compared to laboratory-adapted strains with regard to the induction of type I IFN, they found that both street strains and laboratory strains inhibit TBK1-mediated signaling, but only the P protein of street strains also interacts with and inhibits IKKε-inducible IRF3dependent IFNβ expression (88) (Figure 1) . Middle east respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3

abstract:
  The immune system protects the organism against infections and the damage associated with them. The first line of defense against pathogens is the innate immune response. In the case of a viral infection, it induces the interferon (IFN) signaling cascade and eventually the expression of type I IFN, which then causes an antiviral state in the cells. However, many viruses have developed strategies to counteract this mechanism and prevent the production of IFN. In order to modulate or inhibit the IFN signaling cascade in their favor, viruses have found ways to interfere at every single step of the cascade, for example, by inducing protein degradation or cleavage, or by mediate protein polyubiquitination. In this article, we will review examples of viruses that modulate the IFN response and describe the mechanisms they use.


id: cord-312886-o3ipzn05
title: Antiviral innate immunity and stress granule responses
author: Onomoto, Koji
date: 2014-08-19
txt: ./txt/cord-312886-o3ipzn05.txt
cache: ./cache/cord-312886-o3ipzn05.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S1471490614001276
doi: 10.1016/j.it.2014.07.006
summary:
  Viral infection and stress granules Viral invasion and replication are detected by innate immune sensors in cells, triggering downstream signaling pathways that can ultimately result in the activation of systemic immune responses. In some cases these bodies have been given different names in an attempt to distinguish them from SGs; in this review, however, we refer to virusinduced SG-like granules collectively as SGs. Many viruses induce SGs through the activation of the eukaryotic translation initiation factor (eIF)2a kinases PKR and, in some cases, general control non-depressible 2 (GCN2), which are both triggered by detection of RNA in the cytoplasm [28] ( Figure 2 ). In the stress-recovered condition, GADD34 protein is rapidly downregulated by an unknown mechanism and the phosphorylated form of eIF2a reaccumulates in the cells, resulting in an oscillating pattern of SGs. In cases where viral infection appears to not induce SGs, accumulating evidence suggest that these viruses inhibit SG formation.

abstract:
  Viral infection triggers the activation of antiviral innate immune responses in mammalian cells. Viral RNA in the cytoplasm activates signaling pathways that result in the production of interferons (IFNs) and IFN-stimulated genes. Some viral infections have been shown to induce cytoplasmic granular aggregates similar to the dynamic ribonucleoprotein aggregates termed stress granules (SGs), suggesting that these viruses may utilize this stress response for their own benefit. By contrast, some viruses actively inhibit SG formation, suggesting an antiviral function for these structures. We review here the relationship between different viral infections and SG formation. We examine the evidence for antiviral functions for SGs and highlight important areas of inquiry towards understanding cellular stress responses to viral infection.


id: cord-312892-p72zwmtb
title: RNA sensors of the innate immune system and their detection of pathogens
author: Chen, Nanhua
date: 2017-04-04
txt: ./txt/cord-312892-p72zwmtb.txt
cache: ./cache/cord-312892-p72zwmtb.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1002/iub.1625
doi: 10.1002/iub.1625
summary:
  It in turn causes the multimerization of cytoplasmic TIR domains, which will recruit downstream adaptors TRIF or MyD88 through homotypic interaction, further forming signaling complex called signalosome and activating downstream transcription factors: one is NF-jB that induces proinflammtory cytokines, another is interferon regulatory factor (IRF) that induces anti-viral type I Interferon (IFN) (6) . The summary of cellular localizations and distributions, ligand recognitions, activation mechanisms, cell signaling, recognition of pathogens, and cross-talks for RNA PRRs (2) TLR3 (2) RIG-I (2) The understanding of RNA PRR immune biology including the ligand recognitions, cellular localizations, cell signaling pathways, mechanisms of activation, recognized pathogens and the interactions between different RNA PRRs will definitely be helpful to improve the anti-viral immune response. Third, TLR3, 7, 8 are primarily expressed by macrophages and DCs and recognize viral RNA within the endosomal compartment, whereas RLRs (RIG-I, MDA5) and NLRs (NLRP3, NOD2) are ubiquitously expressed and sense viral RNA within the cytoplasm of infected cells (Table 1 ).

abstract:
  The innate immune system plays a critical role in pathogen recognition and initiation of protective immune response through the recognition of pathogen associated molecular patterns (PAMPs) by its pattern recognition receptors (PRRs). Nucleic acids including RNA and DNA have been recognized as very important PAMPs of pathogens especially for viruses. RNA are the major PAMPs of RNA viruses, to which most severe disease causing viruses belong thus posing a tougher challenge to human and animal health. Therefore, the understanding of the immune biology of RNA PRRs is critical for control of pathogen infections especially for RNA virus infections. RNA PRRs are comprised of TLR3, TLR7, TLR8, RIG‐I, MDA5, NLRP3, NOD2, and some other minorities. This review introduces these RNA PRRs by describing the cellular localizations, ligand recognitions, activation mechanisms, cell signaling pathways, and recognition of pathogens; the cross‐talks between various RNA PRRs are also reviewed. The deep insights of these RNA PRRs can be utilized to improve anti‐viral immune response. © 2017 IUBMB Life, 69(5):297–304, 2017


id: cord-313138-y485ev30
title: Defense genes missing from the flight division
author: Magor, Katharine E.
date: 2013-04-24
txt: ./txt/cord-313138-y485ev30.txt
cache: ./cache/cord-313138-y485ev30.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0145305X13001146
doi: 10.1016/j.dci.2013.04.010
summary:
  Whether cause or effect, the lack of TLR8 in avian monocytes/ macrophages likely does contribute to the susceptibility of birds to RNA viruses (West Nile virus, Newcastle disease virus, influenza virus and others) and intracellular bacterial infections, including mycobacteria. The gene encoding RIG-I, DDX58, is not annotated in the chicken genome sequence, and is missing in some fish species, but MDA5 homologues are present in all vertebrate families (Zou et 2009). Riplet/RNF135 is a cytoplasmic E3-ligase identified by yeast two-hybrid as one of the proteins binding RIG-I, and is essential for RIG-I activation in human cell lines upon infection with an RNA virus (Oshiumi et al., 2009; Oshiumi et al., 2010) . The upregulation of IFIT5 following viral infection of chicken cells expressing duck RIG-I ( Barber et al., 2013) or infection of ducks (Vanderven et al., 2012) suggests IFIT5 is an important antiviral effector in avian species.

abstract:
  Birds have a smaller repertoire of immune genes than mammals. In our efforts to study antiviral responses to influenza in avian hosts, we have noted key genes that appear to be missing. As a result, we speculate that birds have impaired detection of viruses and intracellular pathogens. Birds are missing TLR8, a detector for single-stranded RNA. Chickens also lack RIG-I, the intracellular detector for single-stranded viral RNA. Riplet, an activator for RIG-I, is also missing in chickens. IRF3, the nuclear activator of interferon-beta in the RIG-I pathway is missing in birds. Downstream of interferon (IFN) signaling, some of the antiviral effectors are missing, including ISG15, and ISG54 and ISG56 (IFITs). Birds have only three antibody isotypes and IgD is missing. Ducks, but not chickens, make an unusual truncated IgY antibody that is missing the Fc fragment. Chickens have an expanded family of LILR leukocyte receptor genes, called CHIR genes, with hundreds of members, including several that encode IgY Fc receptors. Intriguingly, LILR homologues appear to be missing in ducks, including these IgY Fc receptors. The truncated IgY in ducks, and the duplicated IgY receptor genes in chickens may both have resulted from selective pressure by a pathogen on IgY FcR interactions. Birds have a minimal MHC, and the TAP transport and presentation of peptides on MHC class I is constrained, limiting function. Perhaps removing some constraint, ducks appear to lack tapasin, a chaperone involved in loading peptides on MHC class I. Finally, the absence of lymphotoxin-alpha and beta may account for the observed lack of lymph nodes in birds. As illustrated by these examples, the picture that emerges is some impairment of immune response to viruses in birds, either a cause or consequence of the host-pathogen arms race and long evolutionary relationship of birds and RNA viruses.


id: cord-313957-hviv5zar
title: Viral Ubiquitin and Ubiquitin-Like Deconjugases—Swiss Army Knives for Infection
author: Masucci, Maria Grazia
date: 2020-08-01
txt: ./txt/cord-313957-hviv5zar.txt
cache: ./cache/cord-313957-hviv5zar.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/biom10081137
doi: 10.3390/biom10081137
summary:
  UbL-specific proteases can reverse the modification, supplementing the cellular pools of free UbLs. The attachment of a Ub moiety to the N-terminal Met1 or to an internal Lys residue of the previous Ub (K6, K11, k27,K29,K33,K48 or K63) results in the formation of topologically different poly-Ub chains that, upon recognition by signal transducers contain dedicated binding domains, target the substrates various fates and cellular functions Ubiquitin is the first recognized and best-known member of the family. UbL-specific proteases can reverse the modification, supplementing the cellular pools of free UbLs. The attachment of a Ub moiety to the N-terminal Met1 or to an internal Lys residue of the previous Ub (K6, K11, k27,K29,K33,K48 or K63) results in the formation of topologically different poly-Ub chains that, upon recognition by signal transducers contain dedicated binding domains, target the substrates various fates and cellular functions Ubiquitin is the first recognized and best-known member of the family.

abstract:
  Posttranslational modifications of cellular proteins by covalent conjugation of ubiquitin and ubiquitin-like polypeptides regulate numerous cellular processes that are captured by viruses to promote infection, replication, and spreading. The importance of these protein modifications for the viral life cycle is underscored by the discovery that many viruses encode deconjugases that reverse their functions. The structural and functional characterization of these viral enzymes and the identification of their viral and cellular substrates is providing valuable insights into the biology of viral infections and the host’s antiviral defense. Given the growing body of evidence demonstrating their key contribution to pathogenesis, the viral deconjugases are now recognized as attractive targets for the design of novel antiviral therapeutics.


id: cord-319501-a2x1hvkk
title: A molecular arms race between host innate antiviral response and emerging human coronaviruses
author: Wong, Lok-Yin Roy
date: 2016-01-15
txt: ./txt/cord-319501-a2x1hvkk.txt
cache: ./cache/cord-319501-a2x1hvkk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s12250-015-3683-3
doi: 10.1007/s12250-015-3683-3
summary:
  Particularly, the host pathogen recognition receptors and the signal transduction pathways to mount an effective antiviral response against SARS and MERS coronavirus infection are discussed. This suggests SARS-CoV N may interfere with RNA recognition by host immune sensors such as RIG-I and MDA5 thus achieving suppressive role in IFN production. Our group demonstrated that MERS-CoV ORF4a interacts with PACT, a cellular dsRNA-binding protein that optimally activates RIG-Iand MDA5-induced type I IFN production, in an RNAdependent manner (Siu et al., 2014c) . Infection with SARS-CoV and MERS-CoV has been accompanied with suppression of innate immune response, most notably with the suppression of type I IFN production and signaling pathways. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells Middle East respiratory syndrome coronavirus 4a protein is a double-stranded RNA-binding protein that suppresses pact-induced activation of RIG-I and MDA5 in the innate antiviral response

abstract:
  Coronaviruses have been closely related with mankind for thousands of years. Communityacquired human coronaviruses have long been recognized to cause common cold. However, zoonotic coronaviruses are now becoming more a global concern with the discovery of highly pathogenic severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses causing severe respiratory diseases. Infections by these emerging human coronaviruses are characterized by less robust interferon production. Treatment of patients with recombinant interferon regimen promises beneficial outcomes, suggesting that compromised interferon expression might contribute at least partially to the severity of disease. The mechanisms by which coronaviruses evade host innate antiviral response are under intense investigations. This review focuses on the fierce arms race between host innate antiviral immunity and emerging human coronaviruses. Particularly, the host pathogen recognition receptors and the signal transduction pathways to mount an effective antiviral response against SARS and MERS coronavirus infection are discussed. On the other hand, the counter-measures evolved by SARS and MERS coronaviruses to circumvent host defense are also dissected. With a better understanding of the dynamic interaction between host and coronaviruses, it is hoped that insights on the pathogenesis of newly-identified highly pathogenic human coronaviruses and new strategies in antiviral development can be derived. [Image: see text]


id: cord-319729-6lzjhn8j
author: Tian, Bin
date: 2018-01-19
txt: ./txt/cord-319729-6lzjhn8j.txt
cache: ./cache/cord-319729-6lzjhn8j.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2017.02011
doi: 10.3389/fimmu.2017.02011
summary:
  title: Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. To assess innate immune responses in astrocytes, cells were infected with DRV or B2c at an MOI of 0.1 and the expression of several proteins involved in the MAVS signaling pathway, namely, RIG-I, p-IRF7, STAT1 and IFIT1 (ISG56), was measured by Western blot.

title:
  Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway

abstract:
  Rabies is an ancient disease but remains endemic in most parts of the world and causes approximately 59,000 deaths annually. The mechanism through which the causative agent, rabies virus (RABV), evades the host immune response and infects the host central nervous system (CNS) has not been completely elucidated thus far. Our previous studies have shown that lab-attenuated, but not wild-type (wt), RABV activates the innate immune response in the mouse and dog models. In this present study, we demonstrate that lab-attenuated RABV causes abortive infection in astrocytes, the most abundant glial cells in the CNS. Furthermore, we found that lab-attenuated RABV produces more double-stranded RNA (dsRNA) than wt RABV, which is recognized by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5). Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Notably, lab-attenuated RABV replicates in a manner identical to that of wt RABV in MAVS−/− astrocytes. It was also found that lab-attenuated, but not wt, RABV induces the expression of inflammatory cytokines via the MAVS- p38/NF-κB signaling pathway. These inflammatory cytokines increase the blood–brain barrier permeability and thus enable immune cells and antibodies infiltrate the CNS parenchyma, resulting in RABV control and elimination. In contrast, wt RABV restricts dsRNA production and thus evades innate recognition by RIG-I/MDA5 in astrocytes, which could be one of the mechanisms by which wt RABV evades the host immune response in resident CNS cells. Our findings suggest that astrocytes play a critical role in limiting the replication of lab-attenuated RABV in the CNS.


id: cord-321607-3r736dnk
title: The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response
author: Ezelle, Heather J.
date: 2016-01-08
txt: ./txt/cord-321607-3r736dnk.txt
cache: ./cache/cord-321607-3r736dnk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26760998/
doi: 10.3390/ijms17010074
summary:
  The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. Although cleavage of RNA virus genomes appeared as the most direct mechanism of action, other important pathways have become evident, such as the regulation of host gene expression, stimulation of IFNβ production, activation of the NACHT, LRR, and PYD-containing protein-3 (NLRP3) inflammasome, and maintenance of the cell''s structural barrier to infection [27, 55, 83, 84] . These small RNAs are capable of stimulating RIG-I and MDA5 (melanoma differentiation associated gene-5) to activate mitochondrial antiviral signaling protein (MAVS) and induce the subsequent translocation of interferon regulatory factor 3 (IRF3) to the nucleus to drive transcription of IFNβ.

abstract:
  The interferon (IFN)-regulated endoribonuclease RNase-L is involved in multiple aspects of the antimicrobial innate immune response. It is the terminal component of an RNA cleavage pathway in which dsRNA induces the production of RNase-L-activating 2-5A by the 2′-5′-oligoadenylate synthetase. The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. This leads to IFNβ expression and IL-1β activation respectively, in addition to broader effects on immune cell function. RNase-L is also one of a growing number of innate immune components that interact with the cell cytoskeleton. It can bind to several cytoskeletal proteins, including filamin A, an actin-binding protein that collaborates with RNase-L to maintain the cellular barrier to viral entry. This antiviral activity is independent of catalytic function, a unique mechanism for RNase-L. We also describe here the interaction of RNase-L with the E3 ubiquitin ligase and scaffolding protein, ligand of nump protein X (LNX), a regulator of tight junction proteins. In order to better understand the significance and context of these novel binding partners in the antimicrobial response, other innate immune protein interactions with the cytoskeleton are also discussed.


id: cord-323756-atnrw9ew
title: Sensing Microbial RNA in the Cytosol
author: Vabret, Nicolas
date: 2013-12-25
txt: ./txt/cord-323756-atnrw9ew.txt
cache: ./cache/cord-323756-atnrw9ew.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/24400006/
doi: 10.3389/fimmu.2013.00468
summary:
  When Janeway formulated the theory of pattern recognition in 1989, he proposed that host cells could sense microbial infection owing to receptors able to recognize invariant molecular structures defined as pathogen-associated molecular patterns (PAMPs). They share a similar organization with three distinct domains: (i) a C-terminal repressor domain (RD) embedded within the C-terminal domain (CTD); (ii) a central ATPase containing DExD/H-box helicase domain able to bind RNA; and (iii) a N-terminal tandem CARD domain that mediates downstream signaling, and which is present in RIG-I and MDA5 but absent in LGP2. DDX60 has also been shown to enhance the IFN-I response to RNA and DNA stimulation through formation of complexes with Frontiers in Immunology | Molecular Innate Immunity RIG-I, MDA5, and LGP2 but not with MAVS. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses

abstract:
  The innate immune system faces the difficult task of keeping a fine balance between sensitive detection of microbial presence and avoidance of autoimmunity. To this aim, key mechanisms of innate responses rely on isolation of pathogens in specialized subcellular compartments, or sensing of specific microbial patterns absent from the host. Efficient detection of foreign RNA in the cytosol requires an additional layer of complexity from the immune system. In this particular case, innate sensors should be able to distinguish self and non-self molecules that share several similar properties. In this review, we discuss this interplay between cytosolic pattern recognition receptors and the microbial RNA they detect. We describe how microbial RNAs gain access to the cytosol, which receptors they activate and counter-strategies developed by microorganisms to avoid this response.


id: cord-327000-oyg3oyx1
title: Porcine Epidemic Diarrhea Virus and the Host Innate Immune Response
author: Li, Shasha
date: 2020-05-11
txt: ./txt/cord-327000-oyg3oyx1.txt
cache: ./cache/cord-327000-oyg3oyx1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/pathogens9050367
doi: 10.3390/pathogens9050367
summary:
  This review highlights the immune evasion mechanisms employed by PEDV, which provides insights for the better understanding of PEDV-host interactions and developing effective vaccines and antivirals against CoVs. Porcine epidemic diarrhea virus (PEDV) is the etiological agent of porcine epidemic diarrhea (PED) that causes an acute and highly contagious enteric disease of swine characterized by vomiting, diarrhea, dehydration, and anorexia in pigs of all ages, especially resulting in severe diarrhea and high mortality rate in piglets. Nsp3 is the largest nsp protein, containing two papain-like protease (PLP1 and PLP2) domains, of which PEDV PLP2 acts as a viral deubiquitinase (DUB), to negatively regulate type I IFN signaling [80] . The evasive strategies utilized by PEDV are classified into four major types: (1) inhibition of RLRs-mediated IFN production pathways, (2) inhibition of the activation of transcription factors responsible for IFN induction, (3) disruption of the signal cascades induced by IFN, and (4) hiding its viral RNA to avoid the exposure of viral RNA to immune sensors.

abstract:
  Porcine epidemic diarrhea virus (PEDV), a swine enteropathogenic coronavirus (CoV), is the causative agent of porcine epidemic diarrhea (PED). PED causes lethal watery diarrhea in piglets, which has led to substantial economic losses in many countries and is a great threat to the global swine industry. Interferons (IFNs) are major cytokines involved in host innate immune defense, which induce the expression of a broad range of antiviral effectors that help host to control and antagonize viral infections. PEDV infection does not elicit a robust IFN response, and some of the mechanisms used by the virus to counteract the host innate immune response have been unraveled. PEDV evades the host innate immune response by two main strategies including: 1) encoding IFN antagonists to disrupt innate immune pathway, and 2) hiding its viral RNA to avoid the exposure of viral RNA to immune sensors. This review highlights the immune evasion mechanisms employed by PEDV, which provides insights for the better understanding of PEDV-host interactions and developing effective vaccines and antivirals against CoVs.


id: cord-328252-dk54w8z9
title: Innate Immune Evasion by Human Respiratory RNA Viruses
author: Kikkert, Marjolein
date: 2019-10-14
txt: ./txt/cord-328252-dk54w8z9.txt
cache: ./cache/cord-328252-dk54w8z9.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1159/000503030
doi: 10.1159/000503030
summary:
  Whether PA-X also degrades viral dsRNA species to prevent recognition by cytosolic RNA sensors is not entirely clear, but mutant viruses in which this PA-X protein was expressed in significantly lower amounts elicited higher levels of innate immune response; for example, IFN-beta production was much higher in these infections [71] . This indeed suggests that PA-X, besides having a role in the degradation of cellular mRNAs, may also degrade viral RNA to prevent recognition by innate immune sensors and activation of innate immune responses, similar to what was shown for the CoVs. To my knowledge, an endoribonuclease has not been identified in the RSV genome, so this virus may use alternative innate immune evasion strategies, as discussed elsewhere in this review. [91] suggested that RSV specifically targets mRNA encoding surfactant protein A, an innate immune factor with an important role in the epithelial tissue of the lung, which directly binds to virus particles to cause their destruction by host defense mechanisms.

abstract:
  The impact of respiratory virus infections on the health of children and adults can be very significant. Yet, in contrast to most other childhood infections as well as other viral and bacterial diseases, prophylactic vaccines or effective antiviral treatments against viral respiratory infections are either still not available, or provide only limited protection. Given the widespread prevalence, a general lack of natural sterilizing immunity, and/or high morbidity and lethality rates of diseases caused by influenza, respiratory syncytial virus, coronaviruses, and rhinoviruses, this difficult situation is a genuine societal challenge. A thorough understanding of the virus-host interactions during these respiratory infections will most probably be pivotal to ultimately meet these challenges. This review attempts to provide a comparative overview of the knowledge about an important part of the interaction between respiratory viruses and their host: the arms race between host innate immunity and viral innate immune evasion. Many, if not all, viruses, including the respiratory viruses listed above, suppress innate immune responses to gain a window of opportunity for efficient virus replication and setting-up of the infection. The consequences for the host's immune response are that it is often incomplete, delayed or diminished, or displays overly strong induction (after the delay) that may cause tissue damage. The affected innate immune response also impacts subsequent adaptive responses, and therefore viral innate immune evasion often undermines fully protective immunity. In this review, innate immune responses relevant for respiratory viruses with an RNA genome will briefly be summarized, and viral innate immune evasion based on shielding viral RNA species away from cellular innate immune sensors will be discussed from different angles. Subsequently, viral enzymatic activities that suppress innate immune responses will be discussed, including activities causing host shut-off and manipulation of stress granule formation. Furthermore, viral protease-mediated immune evasion and viral manipulation of the ubiquitin system will be addressed. Finally, perspectives for use of the reviewed knowledge for the development of novel antiviral strategies will be sketched.


id: cord-328549-r56lih8j
title: Regulation of RIG-I Activation by K63-Linked Polyubiquitination
author: Okamoto, Masaaki
date: 2018-01-05
txt: ./txt/cord-328549-r56lih8j.txt
cache: ./cache/cord-328549-r56lih8j.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29354136/
doi: 10.3389/fimmu.2017.01942
summary:
  First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. However, recent studies have reported three other ubiquitin ligases, RING finger protein leading to RIG-I activation (Riplet), mex-3 RNA-binding family member C (MEX3C), and TRIM4, which are required for the polyubiquitination and activation of RIG-I (28-30).

abstract:
  RIG-I is a pattern recognition receptor and recognizes cytoplasmic viral double-stranded RNA (dsRNA). Influenza A virus, hepatitis C virus, and several other pathogenic viruses are mainly recognized by RIG-I, resulting in the activation of the innate immune responses. The protein comprises N-terminal two caspase activation and recruitment domains (2CARDs), an RNA helicase domain, and the C-terminal domain (CTD). The CTD recognizes 5′-triphosphate viral dsRNA. After recognition of viral dsRNA, the protein harbors K63-linked polyubiquitination essential for RIG-I activation. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. MAVS aggregation then triggers the signal to induce the innate immune responses. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. MEX3C and TRIM4 mediate polyubiquitination of the 2CARDs. By contrast, Riplet ubiquitinates the CTD. The physiological significance of each ubiquitin ligases has been shown by knockout and knockdown studies, but there appears to be contradictory to evidence reported in the literature. In this review, we summarize recent findings related to K63-linked polyubiquitination and propose a model that could reconcile current contradictory theories. We also discuss the physiological significance of the ubiquitin ligases in the immune system against viral infection.


id: cord-341324-f9g9gitn
title: Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway
author: Rojas, José M.
date: 2020-10-21
txt: ./txt/cord-341324-f9g9gitn.txt
cache: ./cache/cord-341324-f9g9gitn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33084946/
doi: 10.1007/s00018-020-03671-z
summary:
  This includes for instance cooperating in PRR recognition of viral PAMPs, stabilizing signaling complexes to improve their resistance to degradation, stopping virus entry, blocking viral capsid formation, impairing trafficking and budding of virions from the infected cells, but also modulating the IFN response to avoid the toxicity of these potent immune mediators. The phosphorylated STAT1/STAT2 heterodimer associates with interferon regulatory factor 9 (IRF9) to form the transcriptional factor complex ISGF3, which translocate to the nucleus and binds the IFN-response elements (ISRE) in ISG promoters leading to the expression of ISG products [36] (Fig. 2 The oligoadenylate synthetase (OAS)-latent RNase (RNase L) pathway is another IFN-inducible pathway that provides the cell with an effector mechanism upon recognition of viral dsRNA (reviewed in [44] ).

abstract:
  Antiviral responses of interferons (IFNs) are crucial in the host immune response, playing a relevant role in controlling viralw infections. Three types of IFNs, type I (IFN-α, IFN-β), II (IFN-γ) and III (IFN-λ), are classified according to their receptor usage, mode of induction, biological activity and amino acid sequence. Here, we provide a comprehensive review of type I IFN responses and different mechanisms that viruses employ to circumvent this response. In the first part, we will give an overview of the different induction and signaling cascades induced in the cell by IFN-I after virus encounter. Next, highlights of some of the mechanisms used by viruses to counteract the IFN induction will be described. And finally, we will address different mechanism used by viruses to interference with the IFN signaling cascade and the blockade of IFN induced antiviral activities.


id: cord-342653-bpyc2gbl
title: Substrate recognition by TRIM and TRIM-like proteins in innate immunity
author: Wang, Hai-Tao
date: 2020-10-20
txt: ./txt/cord-342653-bpyc2gbl.txt
cache: ./cache/cord-342653-bpyc2gbl.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33092958/
doi: 10.1016/j.semcdb.2020.09.013
summary:
  While E3 ligases are often thought to negatively regulate the stability of the target molecule by Ub-mediated proteasomal targeting, many TRIMs have been shown to enhance innate immune signaling pathways [15] , through both proteasome-dependent and -independent mechanisms. The study of RIG-I and RIPLET interaction provides a detailed example of how TRIM-like proteins utilize bivalency and CC for regulating substrate selectivity, higher-order oligomerization and innate immune function. Given that an increasing number of receptors and signaling molecules in the innate immune system are shown to multimerize upon activation [77] , it is tempting to speculate that TRIM/TRIM-like proteins may utilize multimer-specific substrate recognition as a common mechanism for regulating their immune functions. The avidity-driven substrate recognition mechanism of TRIM/TRIM-like proteins would thus ensure more precise control of innate immune signaling and restriction functions.

abstract:
  TRIM (Tripartite motif) and TRIM-like proteins have emerged as an important class of E3 ligases in innate immunity. Their functions range from activation or regulation of innate immune signaling pathway to direct detection and restriction of pathogens. Despite the importance, molecular mechanisms for many TRIM/TRIM-like proteins remain poorly characterized, in part due to challenges of identifying their substrates. In this review, we discuss several TRIM/TRIM-like proteins in RNA sensing pathways and viral restriction functions. We focus on those containing PRY-SPRY, the domain most frequently used for substrate recognition, and discuss emerging mechanisms that are commonly utilized by several TRIM/TRIM-like proteins to tightly control their interaction with the substrates.


id: cord-343824-00mqmpzw
author: Qian, Wei
date: 2017-07-03
txt: ./txt/cord-343824-00mqmpzw.txt
cache: ./cache/cord-343824-00mqmpzw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28717359/
doi: 10.3389/fimmu.2017.00779
summary:
  title: The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-β Production by Targeting TNF Receptor-Associated Factor 3 Influenza A virus non-structural protein 1 (NS1) antagonizes interferon response through diverse strategies, particularly by inhibiting the activation of interferon regulatory factor 3 (IRF3) and IFN-β transcription. Hence, binding of the NS1 protein to dsRNA, RIG-I, and TRIM25 has not established that these NS1 interactions are responsible for inhibiting the activation of IRF3 and IFN transcription. These data reveal a novel mechanism for how the influenza A virus NS1 protein induces inhibition of the host IFN production and may provide a potential target for antiviral drug development. However, our study demonstrated that the influenza A virus NS1 ED targets TRAF3, subsequently inhibits IFN production, implying that TRAF3 is a key factor involved for IAV to escape host innate immune responses.

title:
  The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-β Production by Targeting TNF Receptor-Associated Factor 3

abstract:
  Influenza A virus non-structural protein 1 (NS1) antagonizes interferon response through diverse strategies, particularly by inhibiting the activation of interferon regulatory factor 3 (IRF3) and IFN-β transcription. However, the underlying mechanisms used by the NS1 C-terminal effector domain (ED) to inhibit the activation of IFN-β pathway are not well understood. In this study, we used influenza virus subtype of H5N1 to demonstrate that the NS1 C-terminal ED but not the N-terminal RNA-binding domain, binds TNF receptor-associated factor 3 (TRAF3). This results in an attenuation of the type I IFN signaling pathway. We found that the NS1 C-terminal ED (named NS1/126-225) inhibits the active caspase activation and recruitment domain-containing form of RIG-I [RIG-I(N)]-induced IFN-β reporter activity, the phosphorylation of IRF3, and the induction of IFN-β. Further analysis showed that NS1/126-225 binds to TRAF3 through the TRAF domain, subsequently decreasing TRAF3 K63-linked ubiquitination. NS1/126-225 binding also disrupted the formation of the mitochondrial antiviral signaling (MAVS)–TRAF3 complex, increasing the recruitment of IKKε to MAVS; ultimately shutting down the RIG-I(N)-mediated signal transduction and cellular antiviral responses. This attenuation of cellular antiviral responses leads to evasion of the innate immune response. Taken together, our findings offer an important insight into the interplay between the influenza virus and host innate immunity.


id: cord-343963-99rd3o79
author: Wong, Mun-Teng
date: 2014-12-29
txt: ./txt/cord-343963-99rd3o79.txt
cache: ./cache/cord-343963-99rd3o79.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/25544499/
doi: 10.1038/cmi.2014.127
summary:
  13, 14 Upon infection by viruses such as HCV, viral RNA is first sensed by cellular pattern recognition receptors (PRRs), and the PRR-mediated recruitment of adaptor proteins and the activation of downstream signaling lead to IFN production. First, we briefly discuss the signaling triggered by the retinoic acid-inducible gene 1-like receptor (RLR) and the Toll-like receptor (TLR), which leads to type I IFN synthesis and IFN-mediated signaling pathway activation, resulting in the expression of a variety of effector ISGs. We also summarize the strategies that HCV uses to escape IFN antiviral surveillance. 156 demonstrated that HCVinduced SG formation is IFN-and PKR-dependent and is inversely correlated with the induction of ISG proteins, such as myxovirus resistance gene A (MxA) and Ub-like (UBL)specific protease 18 (USP18), in HCV-infected cells without affecting the mRNA levels of these ISGs. Furthermore, the SG proteins TIA-1, TIAR and G3BP1 have been shown to play a critical role in HCV replication and infectious virus production.

title:
  Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection

abstract:
  Infection with hepatitis C virus (HCV), a major viral cause of chronic liver disease, frequently progresses to steatosis and cirrhosis, which can lead to hepatocellular carcinoma. HCV infection strongly induces host responses, such as the activation of the unfolded protein response, autophagy and the innate immune response. Upon HCV infection, the host induces the interferon (IFN)-mediated frontline defense to limit virus replication. Conversely, HCV employs diverse strategies to escape host innate immune surveillance. Type I IFN elicits its antiviral actions by inducing a wide array of IFN-stimulated genes (ISGs). Nevertheless, the mechanisms by which these ISGs participate in IFN-mediated anti-HCV actions remain largely unknown. In this review, we first outline the signaling pathways known to be involved in the production of type I IFN and ISGs and the tactics that HCV uses to subvert innate immunity. Then, we summarize the effector mechanisms of scaffold ISGs known to modulate IFN function in HCV replication. We also highlight the potential functions of emerging ISGs, which were identified from genome-wide siRNA screens, in HCV replication. Finally, we discuss the functions of several cellular determinants critical for regulating host immunity in HCV replication. This review will provide a basis for understanding the complexity and functionality of the pleiotropic IFN system in HCV infection. Elucidation of the specificity and the mode of action of these emerging ISGs will also help to identify novel cellular targets against which effective HCV therapeutics can be developed.


id: cord-346916-jj4l9ydl
title: Roadblocks and fast tracks: How RNA binding proteins affect the viral RNA journey in the cell
author: Girardi, Erika
date: 2020-08-23
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url: https://api.elsevier.com/content/article/pii/S1084952120300914
doi: 10.1016/j.semcdb.2020.08.006
summary:
  Moreover, despite the molecular mimicry set by RNA viruses to resemble cellular mRNAs and escape host recognition, the viral nucleic acid still needs to embark on a long journey through a hostile cell environment and must overcome the obstacles put in place by the host antiviral system in order to be translated and replicated. Another example, is the zinc-finger antiviral protein (ZAP), which binds vRNAs containing a ZAP response element (ZRE) and induces RNA degradation via interaction of its N-terminal domain with host decay machinery mediated [75] (Fig. 1 ). In fact, IRES elements present in the genome of different families of RNA viruses lack overall conserved features [146, 147] .The classification of viral IRESs in four types stems from their structural organization, their respective dependence on sets of translation initiation factors, and whether they use scanning or instead directly recruit ribosomes to the start codon [148] (Fig. 2) .

abstract:
  As obligate intracellular parasites with limited coding capacity, RNA viruses rely on host cells to complete their multiplication cycle. Viral RNAs (vRNAs) are central to infection. They carry all the necessary information for a virus to synthesize its proteins, replicate and spread and could also play essential non-coding roles. Regardless of its origin or tropism, vRNA has by definition evolved in the presence of host RNA Binding Proteins (RBPs), which resulted in intricate and complicated interactions with these factors. While on one hand some host RBPs recognize vRNA as non-self and mobilize host antiviral defenses, vRNA must also co-opt other host RBPs to promote viral infection. Focusing on pathogenic RNA viruses, we will review important scenarios of RBP-vRNA interactions during which host RBPs recognize, modify or degrade vRNAs. We will then focus on how vRNA hijacks the largest ribonucleoprotein complex (RNP) in the cell, the ribosome, to selectively promote the synthesis of its proteins. We will finally reflect on how novel technologies are helping in deepening our understanding of vRNA-host RBPs interactions, which can be ultimately leveraged to combat everlasting viral threats.


id: cord-350836-1enteev7
title: Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5
author: Brisse, Morgan
date: 2019-07-17
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url: https://doi.org/10.3389/fimmu.2019.01586
doi: 10.3389/fimmu.2019.01586
summary:
  RIG-I (Retinoic acid-inducible gene I) and MDA5 (Melanoma Differentiation-Associated protein 5), collectively known as the RIG-I-like receptors (RLRs), are key protein sensors of the pathogen-associated molecular patterns (PAMPs) in the form of viral double-stranded RNA (dsRNA) motifs to induce expression of type 1 interferons (IFN1) (IFNα and IFNβ) and other pro-inflammatory cytokines during the early stage of viral infection. For the former, siRNA-mediated knock-down (110, 111) , cellular knockout (112) and inhibition by viral protein (109, (113) (114) (115) (116) conditions for TRIM25 in multiple cell types have been shown to change RIG-I cellular localization (110) and to negatively affect RIG-I K63 ubiquitination, association with MAVS and IFN signaling [when the constitutively active RIG-I CARD domain was overexpressed (109, (112) (113) (114) (115) (116) or during viral infection (109, 111, 114) ].

abstract:
  RIG-I (Retinoic acid-inducible gene I) and MDA5 (Melanoma Differentiation-Associated protein 5), collectively known as the RIG-I-like receptors (RLRs), are key protein sensors of the pathogen-associated molecular patterns (PAMPs) in the form of viral double-stranded RNA (dsRNA) motifs to induce expression of type 1 interferons (IFN1) (IFNα and IFNβ) and other pro-inflammatory cytokines during the early stage of viral infection. While RIG-I and MDA5 share many genetic, structural and functional similarities, there is increasing evidence that they can have significantly different strategies to recognize different pathogens, PAMPs, and in different host species. This review article discusses the similarities and differences between RIG-I and MDA5 from multiple perspectives, including their structures, evolution and functional relationships with other cellular proteins, their differential mechanisms of distinguishing between host and viral dsRNAs and interactions with host and viral protein factors, and their immunogenic signaling. A comprehensive comparative analysis can help inform future studies of RIG-I and MDA5 in order to fully understand their functions in order to optimize potential therapeutic approaches targeting them.


id: cord-351520-c5fi2uoh
title: Regulation of virus-triggered type I interferon signaling by cellular and viral proteins
author: Zhong, Bo
date: 2010-02-01
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url: https://doi.org/10.1007/s11515-010-0013-x
doi: 10.1007/s11515-010-0013-x
summary:
  Recently, we and others identified a new adapter protein called mediator of IRF3 activation (MITA, also known as STING), which plays a critical role in virus-induced type I IFN expression (Ishikawa and Barber, 2008; Zhong et al., 2008) .

abstract:
  Host pattern recognition receptors (PRRs) recognize invading viral pathogens and initiate a series of signaling cascades that lead to the expression of type I interferons (IFNs) and inflammatory cytokines. During the past decade, significant progresses have been made to characterize PRRs such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) and elucidate the molecular mechanisms of TLR- and RLR-mediated signaling. To avoid excessive and harmful immune effects caused by over-activation of these signaling pathways, host cells adopt a number of strategies to regulate them. In addition, invading viruses also employ a variety of mechanisms to inhibit the production of type I IFNs, thereby evading the supervision and clearance by the host. In this review, we briefly summarize the TLR- and RLR-mediated type I IFN signaling and then focus on the mechanisms by which host cellular and viral components regulate the expression of type I IFNs.


id: cord-355839-o0m71kvw
author: Sedeyn, Koen
date: 2019-10-17
txt: ./txt/cord-355839-o0m71kvw.txt
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url: https://www.ncbi.nlm.nih.gov/pubmed/31622448/
doi: 10.1371/journal.ppat.1007984
summary:
  ATF2, activating transcription factor 2; CDS, cytoplasmic DNA sensor; ER, endoplasmic reticulum; IFN, interferon; IKK, inhibitor of nuclear factor kappa-B kinase; IKKε, inhibitor of nuclear factor kappa-B kinase subunit epsilon; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated protein 5; MyD88, myeloid differentiation primary response protein MyD88; NF-kB, nuclear factor-kappa B; NOD2, nucleotide-binding oligomerization domain-containing protein 2; PAMP, pathogenassociated molecular pattern; PRR, pattern recognition receptor; RIG, retinoic-acid-inducible gene-I; RLR, RIG-I-like receptor; RSV, respiratory syncytial virus; STING, stimulator of interferon protein; TBK1, tank binding kinase 1; TICAM1, toll/interleukin-1 receptor domain-containing adapter molecule 1; TIRAP, toll/ interleukin-1 receptor domain-containing adapter protein; TLR, toll-like receptor; TRAF3, tumor necrosis factor receptor-associated factor 3; TRAF6, tumor necrosis factor receptor-associated factor 6; TRAM, toll-like receptor adaptor molecule.

title:
  Respiratory syncytial virus nonstructural proteins 1 and 2: Exceptional disrupters of innate immune responses

abstract:
  Human respiratory syncytial virus (RSV) is the most important cause of acute lower respiratory tract disease in infants worldwide. As a first line of defense against respiratory infections, innate immune responses, including the production of type I and III interferons (IFNs), play an important role. Upon infection with RSV, multiple pattern recognition receptors (PRRs) can recognize RSV-derived pathogen-associated molecular patterns (PAMPs) and mount innate immune responses. Retinoic-acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) have been identified as important innate receptors to mount type I IFNs during RSV infection. However, type I IFN levels remain surprisingly low during RSV infection despite strong viral replication. The poor induction of type I IFNs can be attributed to the cooperative activity of 2 unique, nonstructural (NS) proteins of RSV, i.e., NS1 and NS2. These viral proteins have been shown to suppress both the production and signaling of type I and III IFNs by counteracting a plethora of key host innate signaling proteins. Moreover, increasing numbers of IFN-stimulated genes (ISGs) are being identified as targets of the NS proteins in recent years, highlighting an underexplored protein family in the identification of NS target proteins. To understand the diverse effector functions of NS1 and NS2, Goswami and colleagues proposed the hypothesis of the NS degradasome (NSD) complex, a multiprotein complex made up of, at least, NS1 and NS2. Furthermore, the crystal structure of NS1 was resolved recently and, remarkably, identified NS1 as a structural paralogue of the RSV matrix protein. Unfortunately, no structural data on NS2 have been published so far. In this review, we briefly describe the PRRs that mount innate immune responses upon RSV infection and provide an overview of the various effector functions of NS1 and NS2. Furthermore, we discuss the ubiquitination effector functions of NS1 and NS2, which are in line with the hypothesis that the NSD shares features with the canonical 26S proteasome.


