key: cord-0716160-fh9zvfnm authors: Kesheh, Mina Mobini; Mahmoudvand, Shahab; Shokri, Somayeh title: Long noncoding RNAs in respiratory viruses: A review date: 2021-07-12 journal: Rev Med Virol DOI: 10.1002/rmv.2275 sha: 15d17653433a644fb07d1bccef135b26064463e8 doc_id: 716160 cord_uid: fh9zvfnm Long noncoding RNAs (lncRNAs) are defined as RNA molecules longer than 200 nucleotides that can regulate gene expression at the transcriptional or post‐transcriptional levels. Both human lncRNAs and lncRNAs encoded by viruses can modulate the expression of host genes which are critical for viral replication, latency, activation of signalling pathways, cytokine and chemokine production, RNAi processing, expression of interferons (IFNs) and interferon‐stimulated genes (ISGs). Studies on lncRNAs as key regulators of host‐virus interactions may give new insights into therapeutic strategies for the treatment of related diseases. This current review focuses on the role of lncRNAs, and their interactions with respiratory viruses including influenza A virus (IAV), respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Noncoding RNAs (ncRNAs) are functional RNA molecules that are transcribed from mammalian genomic DNA but are unable to encode proteins. 7 The ncRNAs are classified into two major groups including small ncRNAs (∼20 to 200 nucleotides) and long ncRNAs (200 nucleotides to ∼100 kilobases). 8, 9 These noncoding elements constitute nearly 80% of the human genome. 10 MicroRNAs (miRNAs) are one of the small single-stranded ncRNAs (18-25 nucleotides in length) that regulate around 60% of human protein-coding genes. 11, 12 These molecules play an important role in regulating a great number of biological processes such as development, differentiation, growth, metabolism, stress response, angiogenesis, apoptosis and immune response. [13] [14] [15] The miRNAs inhibit transcription and protein synthesis by binding to the 3 0 untranslated region (3 0 UTR) of messenger RNAs (mRNAs). 16 5 0 UTR and the coding regions of mRNA are the sites other than 3 0 UTR that have the potential to interact with miRNAs, giving rise to translational suppression or target gene degradation. 17, 18 LncRNAs are a new class of noncoding RNAs that has emerged as novel players in the regulation of gene expression. 19, 20 Unlike miR-NAs, which primarily rely on base complementarity to interact with their target RNAs, lncRNAs employ diverse mechanisms for regulating biological processes. 21 LncRNAs can regulate gene expression at the level of transcription, RNA processing, or translation, so lncRNA subcellular localisation provides important clues to its potential mode of action. 22 Recently, it has been reported that lncRNAs play important roles during viral infections and subsequently the antiviral immune response. [23] [24] [25] [26] Table 1 and Figures 1 and 2 show lncRNAs involved in immune responses and respiratory viral replication. IAVs are important veterinary and human health pathogens that are present worldwide. 27, 28 After 1918 IAV pandemic (H1N1) with 500 million infected cases and at least 50 million death, influenza pandemics occurred again in 1957 (H2N2), 1968 (H3N2), 1977 (H1N1) and 2009 (H1N1). 29, 30 In IAV infection, the expression of thousands of lncRNAs is altered in host cells. 23 In vitro and in vivo models showed that after IAV infection especially in lung cells, according to corresponding retinoic acid-inducible gene I (RIG-I)-dependent signalling pathway and following interferon beta (IFN-β) induction, the level of interferon-stimulated lncRNA (lncRNA ISR) increased and it was able to suppress viral replication. 31, 32 ISG20 belongs to the 3 0 -5 0 exonuclease super family that displays effective antiviral activity against several RNA viruses, including IAV. ISG20 inhibits the replication of IAV by interacting with viral NP protein and inhibiting viral polymerase activity. [33] [34] [35] Translation of ISG20 can be regulated by binding miRNA-326 (miR-326) to 3 0 UTR of ISG20 mRNAs. In this regard, Chai et al. 23 showed that IAV increases the expression of an interferon-inducible lncRNA termed lnc-ISG20. The lnc-ISG20 showed an inhibitory role on IAV replication by binding to miR-326 to enhance ISG20 protein levels. Zhao et al. 36 Tripartite motif containing 25 (TRIM25) mediates K63-linked ubiquitination of the cytosolic pattern recognition receptor RIG-I which is an essential step for initiation of the intracellular antiviral response. 37, 38 At the early stage of RNA virus infections such as IAV and vesicular stomatitis virus (VSV), a lncRNA called Lnc-zc3h7a by binding to TRIM25 and the helicase domain of activated RIG-1 leads to stabilising TRIM25-activated RIG-I complex. While RIG-I is not activated by lnc-zc3h7a and this lncRNA only binds to the domain which is exposed after RIG-I activation. The produced level of type 1 IFNs and interleukin 6 (IL-6) in serum was significantly less in lnc-zc3h7a−/− mice compared to lnc-zc3h7a+/+ mice as a result of a response to these RNA viruses. 39, 40 The lncRNAs can remotely regulate antiviral genes by relocating or competitively binding to gene repressors. 41 Splicing factor proline and glutamine rich (SFPQ), also known as PSF (PTB-associated splicing factor), is a multifunctional nuclear protein first identified as a splicing factor, that is implicated in many aspects of nuclear functions including RNA transport, apoptosis and DNA repair, transcriptional regulation and maintenance of genome stability. 42,43 Imamura et al. 44 showed that SFPQ bound to its SFPQ-binding motif on IL-8 promoter, led to repressed IL-8 gene expression in naive cells. During IAV infection, increased expression of nuclear paraspeckle assembly transcript 1 (NEAT1) leads SFPQ to relocate from its promoter and recruit into the paraspeckles (a type of subnuclear bodies built on the long noncoding RNA NEAT1). Therefore, transcriptional activation of the antiviral gene IL-8 was increased. As a result, NEAT1 induction followed by excess formation of paraspeckles caused to transcribe more IL-8 mRNAs. Also SFPQ is also an essential factor for influenza virus mRNA polyadenylation. 44, 45 Barriocanal et al. 46 reported that lnc-ISG15 and lnc-BST2/BISPR as IFN-stimulated lncRNAs increased in infected cells by mutant IAV T A B L E 1 A list of lncRNAs and their functions which are involved in immunity responses and respiratory viral replication PSMB8-AS1 has the binding site for regulating miRNAs, such as miR-382-3p. 54 The upregulation of PSMB8-AS1 can modulate the secretion of IL-6 and tumour necrosis factor (TNF) α, two pivotal proinflammatory cytokines. 55 The influenza RNA-dependent RNA polymerase (RdRp) is a trimeric complex comprising three subunits; P1 (or PB1), P2 (or PA) and P3 (or PB2). PB1 is the catalytic core of the polymerase complex responsible for the polymerase activity. 60 Wang et al. 61 SeV, or murine parainfluenza virus type 1, typically infects the respiratory tract of rodents. 69 (C-C motif chemokine ligand 5) and IL-6. 71 Expression of lnc-EPS after entry of SeV is suppressed in bone marrow-derived macrophages to initiate innate immunity cells activity. 72 LncATV, a human specific lncRNA, was relatively highly expressed in human monocytes, erythroleukemia cells and hepatoma cells. LncATV was upregulated upon Type I and III IFN stimulations and virus infection. RIG-I antiviral signalling and IFN effective pathway were inhibited by overexpressed lncATV. 73 Lnc-ATV promoted the replication of Newcastle disease virus (NDV) and SeV through disrupting the production of Type I IFN and ISGs. 74 This finding reveals that lncATV acts as a restricting innate immune response. RSV is a respiratory virus that causes serious and complicated outcomes in infants, and the elderly. 75 suggested that lnc-n337374 inhibited DCs maturation by downregulation of CD86 and pERK1/2. 82 Plasmacytoma variant translocation 1 (PVT1) is an lncRNA that has been found in a variety of cancers. 83 Yu et al. 84 indicated that lnc-PVT1 is involved in the function of α-asarone in treating RSVinduced asthma. Lnc-PVT1 was identified as a molecular sponge of miR-203a. 85 The miR-203a targets the 3 0 -untranslated region of E2F transcription factor 3 (E2F3), a positive regulator, that be involved in DNA replication by stimulating the entry of quiescent cells into the G1/S phase of the cell cycle. 86, 87 Therefore, down regulation of lnc-PVT1 has positive effect on the treatment of RSV infection. The first line of host defence mechanism is innate immunity. 88 In the and involved in the protection of the host against viral infections. 89, 90 IBV is a contagious avian coronavirus that can infect respiratory tract of chicken and in poultry industry is a major problem. 91 Zhang et al. 92 showed that chicken MBL by the interaction to S1 spike protein of IBV plays a role in innate and the adaptive immune response. In avian bone marrow-derived dendritic cells (BMDCs) infected with IBV, levels of two lncRNAs MANBAL and POMT2 were downregulated. Both lncRNAs were associated with mannose, a possible receptor for viral entry. 93 SARS is a viral respiratory illness caused by SARS-associated coronaviruses (SARS-CoVs). SARS-CoV was first identified at the end of Apart from the role of MALAT1 in reduction of IFN signalling, this lncRNA could absorb miR-146a-5p and miR-142-3p to repress their anti-inflammatory function and its overexpression, promoting inflammatory response. 103 Recent studies have shown that exaggerated inflammatory responses and inflammatory cytokine storm leads to acute respiratory distress syndrome (ARDS) aggravation and even death. As listed in Table 2 , lncRNAs are implicated in inflammatory cytokine storm and inflammatory complex including IL-6, TNF-α and NLRP3 inflammasome. 108, 109 In patients that infected by SARS-CoV-2, lncRNAs through inflammatory pathways including TLR signal transduction and NF-κB signalling pathway, leading to host autoimmunity. 110 Specific lncRNAs can be potential candidates to treat Covid-19. A recent study described that four lncRNAs (H19, Hotair, Fendrr and LINC05) directly interact with spike transcript (mRNA) and viral genome. 111 Targeting these lncRNAs involved in innate immune responses could affect the silencing function of miRNAs to provide another treatment strategy for Covid-19. Human adenovirus (HAdV) are an important cause of mild upper respiratory symptoms and they can also infect lower respiratory tract, causing pneumonia and bronchitis. 112 The life cycle of adenovirus can be divided into two phases, an early and a late phase, which are separated by viral DNA replication. The early phase covers the regulation of the cell cycle and suppression of the cellular antiviral response, whereas the late phase covers making gene products that are related to production and assembly of capsid proteins. 113 PKR is an interferon-inducible serine-threonine protein kinase activated in infected cells as part of the antiviral response. Ad5 encodes two virus-associated (VA) RNAs, VAI and VAII. These VA RNAs are lncRNA that fold into a dsRNA with a well-conserved structure. VA RNA I binds to PKR and inhibits its function. 5,116 RNA interference (RNAi) with two key players, Dicer and Argonaute, act to digest viral RNAs. 117 The interference of VARNAI and RNAII with Dicer activity block the RNAi processing pathway. 5 Therefore, the increased viral replication may affect the severity of the disease. 117 HBoV is a respiratory pathogen with four genotype HBoV1-4 that Viral journeys on the intracellular highways The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit Long noncoding RNA and its role in virus infection and pathogenesis Roles of LncRNAs in viral infections Relationship of long noncoding RNA and viruses Viral lncRNA: a regulatory molecule for controlling virus life cycle Non-coding RNA: what is functional and what is junk? Front Genet Roles, functions, and mechanisms of long non-coding RNAs in cancer On the classification of long non-coding RNAs Roles of non-coding RNAs in transcriptional regulation The microRNA (miRNA): overview of the RNA genes that modulate gene function MicroRNA in control of gene expression: an overview of nuclear functions Regulation of influenza virus infection by microRNAs Host microRNAs and exosomes that modulate influenza virus infection miRNA-based strategy for modulation of influenza A virus infection Overview of MicroRNA biogenesis, mechanisms of actions, and circulation A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence Oncogenic role of microRNA-532-5p in human colorectal cancer via targeting of the 5'UTR of RUNX3 lncRNAs regulate innate immune responses and their roles in macrophage polarization Long noncoding RNAs as regulators of Toll-like receptor signaling and innate immunity Immunobiology of long noncoding RNAs Emerging role of long noncoding RNAs as regulators of innate immune cell development and inflammatory gene expression Lnc-ISG20 inhibits influenza A virus replication by enhancing ISG20 expression Evaluation of plasma TRB3 and sestrin 2 levels in obese and normal-weight children lncRNAs regulate the innate immune response to viral infection Long noncoding RNAs in innate immunity Detection of avian influenza virus: a comparative study of the in silico and in vitro performances of current RT-qPCR assays Pandemic potential of highly pathogenic avian influenza clade 2.3.4.4 A(H5) viruses Influenza pandemics of the 20th century Identification of an interferonstimulated long noncoding RNA (LncRNA ISR) involved in regulation of influenza A virus replication Diverse roles of long noncoding RNAs in viral diseases Influenza A Virus-induced expression of ISG20 inhibits viral replication by interacting with nucleoprotein Mammalian and avian host cell influenza A restriction factors. Viruses The interferon-induced exonuclease ISG20 exerts antiviral activity through upregulation of type I interferon response proteins. mSphere A long non-coding RNA IVRPIE promotes host antiviral immune responses through regulating interferon β1 and ISG expression TRIM25 in the regulation of the antiviral innate immunity To TRIM the immunity: from innate to adaptive immunity The long noncoding RNA Lnczc3h7a promotes a TRIM25-mediated RIG-I antiviral innate immune response TRIM25 and its emerging RNA-binding roles in antiviral defense Gene regulation by long non-coding RNAs and its biological functions Splicing factor prolineand glutamine-rich (SFPQ) protein regulates platinum response in ovarian cancer-modulating SRSF2 activity The emerging role of the RNAbinding protein SFPQ in neuronal function and neurodegeneration Long noncoding RNA NEAT1-dependent SFPQ relocation from promoter region to paraspeckle mediates IL8 expression upon immune stimuli Organization and function of paraspeckles Long non-coding RNA BST2/BISPR is induced by IFN and regulates the expression of the antiviral factor tetherin Is tetherin a true antiviral: the influenza a virus controversy LncRNAs in the type I interferon antiviral response Long noncoding RNAs: novel regulators of virus-host interactions NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferonstimulated gene transcription Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors Self-recognition of an inducible host lncRNA by RIG-I feedback restricts innate immune response Roles of lncRNAs in influenza virus infection LncRNA PSMB8-AS1 contributes to pancreatic cancer progression via modulating miR-382-3p/STAT1/PD-L1 axis Characterization of long non-coding RNAs in systemic sclerosis monocytes: a potential role for PSMB8-AS1 in altered cytokine secretion Long non-coding RNA PSMB8-AS1 regulates influenza virus replication Identification of lncRNA-155 encoded by MIR155HG as a novel regulator of innate immunity against influenza A virus infection Protein tyrosine phosphatase 1B is a key regulator of IFNAR1 endocytosis and a target for antiviral therapies Long noncoding RNA AVAN promotes antiviral innate immunity by interacting with TRIM25 and enhancing the transcription of FOXO3a Mapping the domain structure of the influenza A virus polymerase acidic protein (PA) and its interaction with the basic protein 1 (PB1) subunit Influenza virus exploits an interferonindependent lncRNA to preserve viral RNA synthesis through stabilizing viral RNA polymerase PB1 An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism. Science Host long noncoding RNA lncRNA-PAAN regulates the replication of influenza A virus Evidence for a crucial role of a host non-coding RNA in influenza A virus replication Long noncoding RNA lnc-MxA inhibits beta interferon transcription by forming RNA-DNA triplexes at its promoter Long noncoding RNA EGOT negatively affects the antiviral response and favors HCV replication Long non-coding RNAs: regulators of viral infection and the interferon antiviral response Silico analysis of altered expression of long non-coding RNA in SARS-CoV-2 infected cells and their possible regulation by STAT1, STAT3 and interferon regulatory factors Sendai virus, an RNA virus with no risk of genomic integration, delivers CRISPR/Cas9 for efficient gene editing Transcriptome analysis identifies the potential roles of long non-coding RNAs during parainfluenza virus infection LncRNAs and immunity: coding the immune system with noncoding oligonucleotides A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to restrain inflammation A human long non-coding RNA LncATV promotes virus replication through restricting RIG-I-mediated innate immunity RIG-I-like receptors: their regulation and roles in RNA sensing Rapid and simple molecular tests for the detection of respiratory syncytial virus: a review Molecular epidemiology of respiratory syncytial virus Long noncoding RNA NRAV promotes respiratory syncytial virus replication by targeting the MicroRNA miR-509-3p/rab5c Axis to regulate vesicle transportation LncRNA-MEG3 inhibits activation of hepatic stellate cells through SMO protein and miR-212 Research on the correlation of changes in plasma lncRNA MEG3 with change in inflammatory prognosis in patients with traumatic brain injury LncRNA MEG3 ameliorates respiratory syncytial virus infection by suppressing TLR4 signaling Non-coding RNAs and their role in respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections Long-chain non-coding RNA n337374 relieves symptoms of respiratory syncytial virus-induced asthma by inhibiting dendritic cell maturation via the CD86 and ERK pathway lncRNA PVT1 promotes tumorigenesis of colorectal cancer by stabilizing miR-16-5p and interacting with the VEGFA/VEGFR1/AKT Axis α-Asarone suppresses the proliferation and migration of ASMCs through targeting the lncRNA-PVT1/miR-203a/E2F3 signal pathway in RSV-infected rats Down-regulation of miR-203a by lncRNA PVT1 in multiple myeloma promotes cell proliferation Expression and prognostic value of E2F3 transcription factor in non-small cell lung cancer Long noncoding RNAs in the regulation of asthma: current research and clinical implications An introduction to immunology and immunopathology Mannosebinding lectin and its genetic variants Status of mannose-binding lectin (MBL) and complement system in COVID-19 patients and therapeutic applications of antiviral plant MBLs Phylogenetic analysis of infectious bronchitis virus circulating in southern China in 2016-2017 and evaluation of an attenuated strain as a vaccine candidate Chicken mannose binding lectin has antiviral activity towards infectious bronchitis virus Microarray analysis of infectious bronchitis virus infection of chicken primary dendritic cells Modulation of the immune response by Middle East respiratory syndrome coronavirus The deadly coronaviruses: the 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling Annotation of long non-coding RNAs expressed in collaborative cross founder mice in response to respiratory virus infection reveals a new class of interferon-stimulated transcripts Interactions between SARS coronavirus 2 papain-like protease and immune system: a potential drug target for the treatment of COVID-19 Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19 Type I interferon regulates the expression of long non-coding RNAs Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients The noncoding and coding transcriptional landscape of the peripheral immune response in patients with COVID-19 Protein coding and long noncoding RNA (lncRNA) transcriptional landscape in SARS-CoV-2 infected bronchial epithelial cells highlight a role for interferon and inflammatory response Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV Antiviral activities of type I interferons to SARS-CoV-2 infection Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial Emerging role of IL-6 and NLRP3 inflammasome as potential therapeutic targets to combat COVID-19: role of lncRNAs in cytokine storm modulation Evolutionarily conserved long non-coding RNA regulates gene expression in cytokine storm during COVID-19 A study of differential circRNA and lncRNA expressions in COVID-19-infected peripheral blood MicroRNAs and long non-coding RNAs as potential candidates to target specific motifs of SARS-CoV-2 Molecular detection of adenoviruses in the sinus tissues of patient by nested-PCR in Shiraz, Southwest Iran Adenovirus core proteins: structure and function Distinct temporal changes in host cell lncRNA expression during the course of an adenovirus infection Long non-coding RNAs: novel players in regulation of immune response upon herpesvirus infection Adenovirus VA RNA-derived miRNAs target cellular genes involved in cell growth, gene expression and DNA repair Dicer functions transcriptionally and posttranscriptionally in a multilayer antiviral defense Induction of immune responses and immune evasion by human bocavirus. Int Arch Allergy Immunol HEXIM1 and NEAT1 long non-coding RNA form a multi-subunit complex that regulates DNAmediated innate immune response Human bocavirus infection of permanent cells differentiated to air-liquid interface cultures activates transcription of pathways involved in tumorigenesis HEXIM1 has different functions within different RNA-protein complexes Long noncoding RNAs in respiratory viruses: A review None. The authors declare that there are no conflict of interests. Mahmoudvand and Somayeh Shokri wrote the first draft of the manuscript and critically revised the manuscript. All authors reviewed and approved the final version of the manuscript. The data that support the findings of this study are openly available in the cited reference. https://orcid.org/0000-0003-4609-3110