key: cord-0892104-sxczn44g
authors: Schultze, Joachim L.; Aschenbrenner, Anna C.
title: COVID-19 and the human innate immune system
date: 2021-02-16
journal: Cell
DOI: 10.1016/j.cell.2021.02.029
sha: cf6249f957ff6cb7ad8674ee5bb31a6d9375217f
doc_id: 892104
cord_uid: sxczn44g

The introduction of SARS-CoV-2 into the human population represents a tremendous medical and economical crisis. Innate immunity - as the first line of defense of our immune system - plays a central role in combating this novel virus. Here, we provide a conceptual framework for the interaction of the human innate immune system with SARS-CoV-2 to link the clinical observations with experimental findings that have been made during the first year of the pandemic. We review evidence that variability in innate immune system components among humans is a main contributor to the heterogeneous disease courses observed for COVID-19, the disease spectrum induced by SARS-CoV-2. A better understanding of the pathophysiological mechanisms observed for cells and soluble mediators involved in innate immunity is a prerequisite for the development of diagnostic markers and therapeutic strategies targeting COVID-19. However, this will also require additional studies addressing causality of events, which is so far lacking behind.

The introduction of SARS-CoV-2 into the human population represents a tremendous medical 23 and economical crisis. Innate immunity -as the first line of defense of our immune system -24 plays a central role in combating this novel virus. Here, we provide a conceptual framework for 25 the interaction of the human innate immune system with SARS-CoV-2 to link the clinical 26 observations with experimental findings that have been made during the first year of the 27 pandemic. We review evidence that variability in innate immune system components among 28 humans is a main contributor to the heterogeneous disease courses observed for COVID-19, 29 the disease spectrum induced by SARS-CoV-2. A better understanding of the 30 pathophysiological mechanisms observed for cells and soluble mediators involved in innate 31

immunity is a prerequisite for the development of diagnostic markers and therapeutic strategies 32 targeting COVID-19. However, this will also require additional studies addressing causality of genetic evolution, variable infectivity or co-pathogenesis might contribute to infectivity and 46

fatality, but not so much to disease heterogeneity observed for COVID-19. While many 47 mutations decreased infectivity, the virus variant D614G in the spike protein of SARS-CoV-2 48 increased infectivity . Two clades, recently emerged in the UK (B.1.1.7) and 49

South Africa (B.1.1.351) similarly increased infectivity. Overall, however, there is little evidence 50

for the virus to be mainly responsible for disease heterogeneity, which leaves the host and the 51 environment as factors influencing disease course and outcome. While there is evidence that 52 environmental factors such as seasonality, other natural disasters, environmental degradation, 53 quality of the public health infrastructure, or governance by state authorities have an impact on 54 overall disease burden for society , the host itself seems to be the major factor 55 explaining disease severity, probably also infection rates (Merad and Martin, 2020; Vabret et al., 56 2020) and long-term medical consequences (Marshall, 2020) . Disease severity and mortality 57 rates are significantly higher in elderly populations pointing toward lack of widespread long-58 lasting pre-existing adaptive immunity by T or B cells against SARS-CoV-2 (Morens and Fauci, 59 2020). This is in stark contrast to the 2009 influenza pandemic, which had much lower incidence 60 rates in the elderly population, indicating partial protection on population level due to earlier 61 exposure to similar influenza viruses (Xu et al., 2010) . It is possible that cross-protection via 62 adaptive immune responses against endemic coronaviruses might be in part responsible for 63 mild disease courses in younger individuals (Lipsitch et al., 2020 ). An effective immune 64 response against SARS-CoV-2 requires both arms of the immune system, the innate immune 65 system (Box 1) including granulocytes, monocytes, and macrophages among other cells of the 66 innate immune system and the adaptive immune system with T and B cells (for adaptive 67 immunity against SARS-CoV-2 see ( In absence of cell type-specific expression maps of SARS-CoV-2 viral entry-associated genes, 135

the Human Cell Atlas (HCA) Lung Biological Network investigated the prevalence of ACE2 and 136 TMPRSS2 in the body by analyzing their expression in single-cell RNA-sequencing data 137

(scRNA-seq) from multiple tissues from healthy human donors (Sungnak et al., 2020) . Probably 138 most important for the high efficacy of SARS-CoV-2 transmission is the high co-expression of 139

ACE2 and TMPRSS2 in nasal epithelial cells, particularly in two types of goblet cells and a 140 subset of ciliated cells, showing the highest expression among all cells in the respiratory tree 141 (Figure 2A ). An interesting observation of this study was the high co-expression of genes 142 involved in early steps of antiviral immune responses in these epithelial cells, which indicated 143 the potential for these specialized nasal cells to play an important role in the initial viral infection, 144

spread, but potentially also clearance. In the lung, ACE2 and TMPRSS2 expression has been 145 mainly identified in alveolar epithelial type II cells Zou et al., 2020) . TMPRSS2 is 146 more widely expressed than ACE2 and cells with simultaneous expression were identified in the 147 respiratory tree, the cornea, esophagus, ileum, colon, gallbladder and common bile duct 148 (Sungnak et al., 2020) , yet there was no evidence for simultaneous expression in immune cells. 149

Extending these studies to even larger datasets including dozens of different scRNA-seq 150 datasets derived from many groups around the world revealed the power of metadata analysis 151 based on scRNA-seq (Muus et al., 2020 Accumulating evidence indicates that SARS-CoV-2 is targeting the type I IFN system at multiple 293 steps thereby strongly interfering with a well-orchestrated interplay between antiviral and 294 proinflammatory innate and adaptive defense mechanisms within the immune system. Studies 295 with more in-depth longitudinal profiling and stratification by disease severity are warranted to 296 clarify the questions surrounding the nature of the early IFN response to SARS-CoV-2. Further 297 dissecting this delicate balance at the early steps of a SARS-CoV-2 infection for each patient 298

individually might be critical to better stratify patients and to allow for patient-tailored treatment 299

options thereby preventing the development of immunopathology as the basis for severe 300 disease courses (Lee and Shin, 2020). 301 302

The next phase -from 'cytokine storm' to immunosuppression All in all, a scenario emerges with rather differently programmed innate immune cells in mild 495 versus severe disease courses (Figure 4) , which is also accompanied with similar differences in 496 the adaptive immune response to SARS-CoV-2 (Sette and Crotty, 2021). Following the initial 497 local innate immune response, the occurrence of a systemic immune response component 498 seems to be independent of disease severity, albeit cellular changes differ dramatically between 499 mild and severe cases. Further, the decision, which kind of innate immune response to this virus 500 will occur seems to be made very early after infection. was proposed that critical illness in COVID-19 is associated with genetic variance in IFNAR2 529

and OAS2, two genes involved in antiviral defence mechanisms, as well as DPP9, TYK2 and 530 CCR2, three genes previously associated with host-driven inflammatory lung injury, of which 531 IFNAR2, DPP9 and CCR2 were also revealed by a transcriptome-wide association study (Pairo-532

Castineira et al., 2020). It needs to be mentioned that these GWAS did not yet reveal any 533 causative relationships and that the odds ratios were rather low, indicating that genetics might 534 only play a minor influence at these gene loci. 535 536

The COVID Human Genetic Effort consortium sequenced genomes from patients with severe 537 COVID-19 and compared them with mild patients. Emphasizing on genes within pathways that 538

were associated with genetic susceptibility for other viral infections, particularly influenza, they 539 identified 13, mainly loss-of-function mutations associated with severe COVID-19 disease 540 course in the TLR3, IRF7, and IRF9 pathways (Zhang et al., 2020a) ( Figure 5) . pDCs from 541 IRF7-deficient patients produced no type I IFN when infected with SARS-CoV-2, and fibroblasts 542 from patients with deficiencies in TLR3, IRF7 and IFNAR1 were susceptible to SARS-CoV-2 543 infection suggesting that cell-autonomous innate immune mechanisms were not operational. 544

The overall estimate for such deficiencies among patients with severe disease was 3.5%. These 545 findings strongly point towards a causal relationship between genotype and phenotype and 546 support an important role for type I IFNs in defense against SARS-CoV-2. The role of the type I 547

IFN system was further underlined by the identification of the presence of a B cell autoimmune 548 phenocopy of inborn type I IFN immunodeficiency in more than 10% of patients with severe 549 COVID-19 (Bastard et al., 2020). Autoantibodies against type I IFN were more prevalent in men, 550

which might contribute to the excess of men among patients with severe COVID-19. The 551

understanding of such immune-phenomena will allow better patient stratification in a precision 552 medicine approach to tailor therapeutic options such as plasmapheresis, plasmablast depletion 553 or early treatment with recombinant type I IFNs for these patients. 554

Another approach identified variants of the X-chromosomal TLR7 as genetic susceptibility 555 factors by performing genetic variance segregation analysis in two families with young family 556 members (<35 years) admitted to the ICU due to severe COVID-19 (van der Made et al., 2020) 557 ( Figure 5) . In both families, the TLR7 mutations resulted in downregulation of downstream 558 genes including IRF7, IFNB1 and ISG15 upon stimulation of PBMCs with the TLR7 ligand 559

imiquimod. As a consequence, production of IFNγ was also decreased. 560 561

Collectively, these findings establish TLR3, TLR7, type I and II IFN responses as important 562

immune mechanisms controlling infection with SARS-CoV-2. Ongoing studies are now 563 addressing whether the assessment of these variants can be integrated in future risk scores 564 used to identify individuals at elevated risk to develop severe COVID-19 or utilized in clinical 565 tests to stratify patients for preventive and novel mechanism-based therapeutic measures. Union and several million individuals have been vaccinated since late 2020. A most surprising 710 finding in light of age-related changes in the adaptive and the innate immune system is the 711 similarly high efficiency of these vaccines in the elderly population. This unexpected success 712 requires further mechanistic and molecular evaluations about the elicited immune response 713 since this might give insights how age-related alterations of the immune system are overcome 714 by this type of vaccination. 715 716

The third strategy is targeting the deviation of the immune response to avoid or mitigate severe 717 and fatal disease outcomes. A starting point for many therapeutic strategies has been the 718 hyperinflammatory state in severe disease Wang et al., 2020a) . Not 719 surprisingly, trials targeting cytokines including IL-6, IL-1, IFNγ, IL-1R, TNF, IL-8, GM-CSF, GM-720 CSF receptor, or IL-37 have been reported, but also strategies attempting to achieve disruption 721 of chemokine signaling, e.g. via CCR1, CCR2, and CCR5 to prevent overt innate immune cell 722 recruitment into the lung (Wang et al., 2020a) . Since COVID-19 presents with such 723 heterogeneity, a certain drug might be beneficial in one setting, while having no effect in 724

another Valuable descriptive and correlative information about COVID-19 has been gathered during the 761 first months of the pandemic (Figure 6) . COVID-19 can be divided in at least five phases 762 (Figure 1) , starting with the infection of ACE2 + epithelial cells of the respiratory tract leading to 763 cell-autonomous defense mechanisms of the infected cells. The second, local immune response 764 phase is characterized by an atypical and heterogeneous type I IFN response due to SARS-765

CoV-2 attacking the IFN system. Further mechanistic insights into the regulation of the 766 heterogeneity of the type I IFN response combined with the elevated expression of NF-kB-767 associated inflammatory genes mainly in severe COVID-19 are urgently needed. Organ 768 involvement, magnitude of clinical symptoms and length of this phase is highly variable and 769 whether the heterogeneity of innate immunity is causally related to the clinical heterogeneity 770 also requires further work. Here, sex differences concerning innate immunity in COVID-19 need 771

to be considered (Takahashi et al., 2020) and molecularly characterized. This is similarly true for 772 a potential role of innate immune cells such as NK cells, innate lymphoid cells, mast cells, 773 basophils or eosinophils, which have not yet been studied in sufficient detail in COVID-19. 774 775

To further improve our knowledge on COVID-19 and in particular on innate immunity against 776 SRAS-CoV-2 infection, future studies need to be tailored to address important questions for 777 each disease phase. To better determine individuals at risk for an incomplete innate immune 778 response during infection and local immunity, risk scores based on genetic findings ( validation studies with longitudinal sampling will ensure sufficiently covered molecular subtypes 793 of COVID-19, which subsequently need to be supported by mechanistic studies in animal 794 models (Mulchandani et al., 2020) . 795

More evidence accumulates suggesting that a yet unknown fraction of patients will suffer from 796 what is described as Long COVID-19, a chronic illness with very heterogeneous symptoms 797 (Marshall, 2020) . These include chronic fatigue syndrome (Salisbury, 2020 ) and a spectrum of 798 psychiatric disorders ranging from cognitive decline, depression to even neurodegeneration 799 J o u r n a l P r e -p r o o f (Taquet et al., 2020) . A better description of the heterogeneity of Long COVID-19 and the 800 underlying molecular mechanisms need to be established to provide therapeutic options for 801 these patients. It will be interesting to see how the immune deviations seen in acute COVID-19 802 extend or further develop in these patients. It will be important to generate large enough 803 registries of individuals suffering from Long COVID-19 to address the mechanisms involved in 804 this heterogeneous syndrome. 805 806

Box 1 -Definition for disease severity, the innate immune system and systems medicine 807 808 COVID-19 disease severity categories: In addition to national categories the WHO disease 809 severity category is widely used. Here, the major categories are mild disease, moderate disease 810 (mainly characterized by pneumonia), severe disease (with severe pneumonia), and critical 811 disease (with acute respiratory distress syndrome (ARDS) and/or sepsis and/or septic shock). A 812 number of other complications have been described particularly for severe and critical disease 813 such as acute pulmonary embolism, acute coronary syndrome, acute stroke or delirium among 814 many others including Guillain-Barré syndrome. 815 816

Innate immune system, innate immune cells, and innate immunity. The immune system is 817 divided into two arms, the adaptive immune system with T and B lymphocytes and the innate 818

immune system with all other immune cell types of which granulocytes, monocytes, 819 macrophages and NK cells are the more common cells, but many other innate immune cells 820 also exist including different dendritic cells, innate lymphoid cells or mast cells. While the 821 majority of all species possess an innate immune system, the conventional adaptive immune 822 system is restricted to jawed vertebrates. While most immune responses involve both the innate 823

immune system and the adaptive immune system evoking innate and adaptive immunity, 824 respectively, the extent to which both arms are recruited to an immune response differs 825 between stimuli. We want to apologize to all those colleagues whose excellent work we could not reference here. 

Dysregulation of type I interferon responses in 946 COVID-19

Erythroid Cells, and Plasmablasts as Hallmarks of Severe

Drives Development of COVID-19

Airway remodeling is absent in CCR1-/-mice during 990 chronic fungal allergic airway disease

Inflamm-aging: autoimmunity, and the immune-risk 992 phenotype

Host-Viral Infection Maps Reveal Signatures of Severe 995 COVID-19 Patients

SARS-CoV-2-reactive T cells in healthy donors and 998 patients with COVID-19

Baricitinib restrains the immune dysregulation in patients 1001 with severe COVID-19

The 1003 dynamic changes in cytokine responses in COVID-19: a snapshot of the current state of 1004 knowledge

The coronavirus is mutating -does it matter?

Influenza-induced production of interferon-alpha is defective in geriatric individuals

Evolution and epidemic spread 1011 of SARS-CoV-2 in Brazil

Neuropilin-1 facilitates SARS-CoV-2 1014 cell entry and infectivity

COVID-19: immunopathology and its implications for therapy

Peripheral immunophenotypes in children with multisystem 1019 inflammatory syndrome associated with SARS-CoV-2 infection

A Global Effort to Define 1021 the Human Genetics of Protective Immunity to SARS-CoV-2 Infection

BCG vaccination in infancy does not 1023 protect against COVID-19. Evidence from a natural experiment in Sweden

Age-related susceptibility to Coronavirus 1025 infections: role of impaired and dysregulated host immunity

Single-Cell Chromatin Modification Profiling 1028 Reveals Increased Epigenetic Variations with

COVID-19 severity correlates with airway 1031 epithelium-immune cell interactions identified by single-cell analysis

The Immunology of Multisystem Inflammatory 1035 Syndrome in Children with COVID-19

The 1037 species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and 1038 naming it SARS-CoV-2

The COVID-19 Host Genetics Initiative, a global 1040 initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-1041

CoV-2 virus pandemic

Remodeling of the 1043 Immune Response With Aging: Immunosenescence and Its Potential Impact on COVID-19

Profile of a killer: the complex biology powering the coronavirus 1046 pandemic

An inflammatory cytokine signature 1049 predicts COVID-19 severity and survival

Basophils enhance 1052 immunological memory responses

Induced Trained Immunity Protects against Leishmania braziliensis Infection: a 1056 Crucial Role for IL-32

BCG vaccine protection from 1058 severe coronavirus disease 2019 (COVID-19)

Cytokine Storm

SARS-CoV-2 Targeting the 1061 Retina: Host-virus Interaction and Possible Mechanisms of Viral Tropism

Sustained cellular immune dysregulation in individuals 1065 recovering from SARS-CoV-2 infection

Immunobiography and the heterogeneity of immune responses in the elderly: A focus on 1068 inflammaging and trained immunity

Inflammaging decreases adaptive and innate immune 1070 responses in mice and humans

Aging, Obesity, and Inflammatory Age-1072 Related Diseases

Mild or Moderate Covid-19

Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-1077 associated lung injury

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly

A SARS-CoV-2 protein interaction map 1088 reveals targets for drug repurposing

Targets of T Cell Responses to 1091 SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

Mapping Systemic Inflammation and Antibody 1095 Responses in Multisystem Inflammatory Syndrome in Children (MIS-C)

Clinical characteristics of coronavirus disease 2019 in China. N. Engl. 1098

Extrapulmonary manifestations of COVID-1101 19

Association Between Early 1104 Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19

Impaired type I interferon activity and 1108 inflammatory responses in severe COVID-19 patients

SARS-CoV-2 Rates in BCG-Vaccinated and 1110 Unvaccinated Young Adults

Lessons learnt from easing COVID-19 restrictions: an 1113 analysis of countries and regions in Asia Pacific and Europe

Baricitinib treatment resolves 1116 lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected 1117 rhesus macaques

SARS-CoV-2 Cell Entry 1120 Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Remodeling of Bone Marrow 1124 Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or 1125 Physiological Aging

Tocilizumab for Covid-19 -The Ongoing Search for 1127 Effective Therapies

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. 1130 Lancet

High dose subcutaneous Anakinra to treat 1134 acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill 1135 COVID-19 patients

Syrian hamsters as a small animal model for 1138 SARS-CoV-2 infection and countermeasure development

Clinical Characteristics and Neonatal 1142 Outcomes of Pregnant Patients With COVID-19: A Systematic Review

Mouse model of SARS-CoV-2 reveals inflammatory role of type I 1146 interferon signaling

Viral load of SARS-CoV-2 across patients 1148 and compared to other respiratory viruses

Synergism of TNF-α and IFN

Tissue Damage, and Mortality in SARS-CoV-2 Infection and 1152 Cytokine Shock Syndromes

Targeting host cell proteases to prevent SARS-CoV-2 invasion

The Architecture of 1156 SARS-CoV-2 Transcriptome

Impact of Routine Infant BCG Vaccination on COVID-19

Bacille Calmette-Guerin 1161 induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming 1162 of monocytes

Incidence of 1165 thrombotic complications in critically ill ICU patients with COVID-19

SARS-CoV-2 ORF3b Is a Potent 1169 Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant

Anakinra 1173 treatment in critically ill COVID-19 patients: a prospective cohort study

Tracking Changes in SARS-CoV-2 Spike: 1176 Evidence that D614G Increases Infectivity of the COVID-19 Virus

Comprehensive mapping of 1181 immune perturbations associated with severe COVID-19

Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive 1183 protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis

A dynamic COVID-19 immune 1187 signature includes associations with poor prognosis

The type I interferon response in COVID-19: implications for 1189 treatment

Immunophenotyping of COVID-19 and influenza highlights the role of 1192 type I interferons in development of severe COVID-19

Activation and evasion of type I interferon responses by SARS-CoV-2

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19

Lack of evidence for BCG vaccine 1200 protection from severe COVID-19

Cross-reactive memory T cells and 1202 herd immunity to SARS-CoV-2

Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized 1205 patients with COVID-19

The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity

Angiotensin-converting enzyme 2 is 1211 a functional receptor for the SARS coronavirus

Clinical and immunological assessment of asymptomatic SARS-CoV-2 1214 infections

Immune signaling by RIG-I-like receptors

Longitudinal analyses reveal immunological misfiring in 1219 severe COVID-19

Presence of Genetic Variants Among Young Men With Severe COVID-19

Cytokine Storms: Understanding COVID-19

Trained Innate Immunity, Epigenetics, and Covid-19

The lasting misery of coronavirus long-haulers

Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential 1231 biological efficacy

Selective and cross-reactive SARS-CoV-2 T cell 1234 epitopes in unexposed humans

Deep immune profiling of 1237 COVID-19 patients reveals distinct immunotypes with therapeutic implications

Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the 1240 transmembrane protease TMPRSS2

Protective role of Toll-like Receptor 3-induced type I interferon in murine coronavirus infection of 1243 macrophages

Coronavirus disease 2019 treatment: A review of early 1245 and emerging options

Pathological inflammation in patients with COVID-19: a key 1247 role for monocytes and macrophages

Decoding type I and III interferon signalling 1249 during viral infection

Ultra-High-Throughput Clinical 1252 Proteomics Reveals Classifiers of COVID-19 Infection

Neutrophil extracellular traps 1255 contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Aging impairs both primary and secondary RIG-I signaling for interferon induction in human 1259 monocytes

COVID-19: What type of cytokine storm are we 1262 dealing with?

Safety 1265 and COVID-19 Symptoms in Individuals Recently Vaccinated with BCG: a Retrospective Cohort 1266 Study

Emerging Pandemic Diseases: How We Got to COVID-1268 19

Escaping Pandora's Box -Another 1270 Novel Coronavirus

Deciphering the COVID-19 1272 cytokine storm: Systematic review and meta-analysis

Integrated analyses of single-cell 1275 atlases reveal age, gender, and smoking status associations with cell type-specific expression 1276 of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target 1277 cells

Defining 1280 trained immunity and its role in health and disease

Trained Immunity: a Tool for Reducing 1283 Susceptibility to and the Severity of SARS-CoV-2 Infection

The host immune response in respiratory 1285 virus infection: balancing virus clearance and immunopathology

Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity

Immune Response Resetting as a Novel 1291 Strategy to Overcome SARS-CoV-2-Induced Cytokine Storm

BCG-induced trained immunity: can it offer protection 1293 against COVID-19?

Interferons and viruses 1296 induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor

Rapid SARS-CoV-2 1300 whole-genome sequencing and analysis for informed public health decision-making in the 1301 Netherlands

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-1304 reactivity with SARS-CoV

The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility 1307 and severity

Genetic mechanisms of critical 1310 illness in Covid-19

Single-1312 cell analysis shows that paracrine signaling by first responder cells shapes the interferon-β 1313 response to viral infection

Severe COVID-19 and aging: are monocytes the key? Geroscience 42

Platelet-Neutrophil Crosstalk 1317 in Atherothrombosis

Safety and Efficacy of the BNT162b2 1320 mRNA Covid-19 Vaccine

COVID-19 and emerging 1323 viral infections: The case for interferon lambda

Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) 1326 in Wuhan, China

Single cell RNA sequencing of 13 human 1328 tissues identify cell types and receptors of human coronaviruses

LifeTime and improving European 1332 healthcare through cell-based interceptive medicine

Multi-layered stochasticity and paracrine signal 1335 propagation shape the type-I interferon response

Dexamethasone in 1338 Hospitalized Patients with Covid-19 -Preliminary Report

Severe immunosuppression and not a 1341 cytokine storm characterizes COVID-19 infections

COVID-19: In the Eye of the 1343

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients 1347 Hospitalized With COVID-19 in the

COVID-19: more 1349 than a cytokine storm

Systems-Level Immunomonitoring from 1352 Acute to Recovery Phase of Severe COVID-19

Existence of SARS-CoV-2 Entry 1355 Molecules in the Oral Cavity

Helen Salisbury: When will we be well again?

Interplay between SARS-CoV-2 1358 and the type I interferon response

Severe COVID-19 Is Marked by a 1361 Dysregulated Myeloid Cell Compartment

Adaptive immunity to SARS-CoV-2 and COVID-19

Genomewide Association 1365 Study of Severe Covid-19 with Respiratory Failure

Cell entry 1367 mechanisms of SARS-CoV-2

Age-dependent dysregulation of 1369 innate immunity

Proteomic and Metabolomic Characterization of COVID-19

Plasma Proteomics Identify Biomarkers and Pathogenesis of COVID-19

Elevated Calprotectin and Abnormal Myeloid 1377 Cell Subsets Discriminate Severe from Mild COVID-19

Trained immunity" from Mycobacterium spp. 1379 exposure or BCG vaccination and COVID-19 outcomes

Is a "Cytokine Storm" Relevant to COVID-1381 19?

Exacerbated innate host response to SARS-CoV in aged non-human primates

A unifying structural and 1388 functional model of the coronavirus replication organelle: Tracking down RNA synthesis

Neuroinvasion of SARS-CoV-2 in human and mouse brain

Efficacy of Tocilizumab in 1395 Patients Hospitalized with Covid-19

SARS-CoV-2 entry factors are highly 1398 expressed in nasal epithelial cells together with innate immune genes

Multi-Omics Resolves a Sharp Disease-State Shift between Mild 1401 and Moderate COVID-19

Sex differences in immune responses that underlie 1404 COVID-19 disease outcomes

Antiviral interferon response at single-cell resolution

Cytokine Storm in COVID-19: 1408 The Current Evidence and Treatment Strategies

Bidirectional associations 1410 between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 1411 cases in the USA

Effect of Dexamethasone on Days 1414 Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress 1415 Syndrome and COVID-19: The CoDEX Randomized Clinical Trial

Immunology of COVID-19: Current State of the Science

Outcomes Associated With Use of a Kinin B2 1421 Receptor Antagonist Among Patients With COVID-19

SARS-CoV-2-triggered 1424 neutrophil extracellular traps mediate COVID-19 pathology

Cytokine storm and leukocyte 1426 changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in 1427 China and emerging pathogenesis and therapy concepts

Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is 1430 Associated with Favorable Clinical Responses in COVID-19 Patients

Association Between Administration of Systemic 1435 Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

A single-cell atlas of the peripheral 1439 immune response in patients with severe COVID-19

Factors associated with COVID-19-related 1442 death using OpenSAFELY

Single-cell analysis 1445 reveals that stochasticity and paracrine signaling control interferon-alpha production by 1446 plasmacytoid dendritic cells

TH17 responses in cytokine storm of COVID-19: An emerging 1448 target of JAK2 inhibitor Fedratinib

A new coronavirus associated with human respiratory disease in China

Evasion of Type I Interferon by SARS-CoV-2

Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood 1456 mononuclear cells in COVID-19 patients

Structural basis 1458 of preexisting immunity to the 2009 H1N1 pandemic influenza virus

Attenuated Interferon and Proinflammatory Response in SARS-CoV-1461 2-Infected Human Dendritic Cells Is Associated With Viral Antagonism of STAT1 1462 Phosphorylation

1464 (2020b). Plasma IP-10 and MCP-3 levels are highly associated with disease severity and 1465 predict the progression of COVID-19

Molecular Architecture of the SARS-CoV-2 Virus

Age-related rhesus macaque models of COVID-19

The major genetic risk factor for severe COVID-19 is 1471 inherited from Neanderthals

A Genomic Perspective on the Origin and Emergence 1473 of SARS-CoV-2

Inborn errors of type I IFN immunity in patients with 1476 life-threatening COVID-19

SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19

Age-related increases in PGD(2) 1481 expression impair respiratory DC migration, resulting in diminished T cell responses upon 1482 respiratory virus infection in mice

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

A human circulating immune cell landscape in aging and COVID-19

Interferon-α2b Treatment for COVID-19

Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell 1494 Responses

SARS-CoV-2 Receptor ACE2 Is an Interferon-1497

Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets 1498 across Tissues

Single-cell RNA-seq data 1500 analysis on the receptor ACE2 expression reveals the potential risk of different human organs 1501 vulnerable to 2019-nCoV infection