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

English version

Autoři: Koen Sedeyn ^aff001; Bert Schepens ^aff001; Xavier Saelens ^aff001
Působiště autorů: VIB-UGent Center for Medical Biotechnology, Ghent, Belgium ^aff001; Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium ^aff002; Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium ^aff003
Vyšlo v časopise: Respiratory syncytial virus nonstructural proteins 1 and 2: Exceptional disrupters of innate immune responses. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1007984
Kategorie: Review
doi: https://doi.org/10.1371/journal.ppat.1007984

Souhrn

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.

Klíčová slova:

Epithelial cells – Immune response – Interferons – Phosphorylation – Respiratory infections – Toll-like receptors – Transcription factors – STAT proteins

Zdroje

1. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375(9725):1545–55. doi: 10.1016/S0140-6736(10)60206-1 20399493; PubMed Central PMCID: PMC2864404.

2. Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. 2017;390(10098):946–58. doi: 10.1016/S0140-6736(17)30938-8 28689664; PubMed Central PMCID: PMC5592248.

3. Collaborators GBDLRI. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis. 2018;18(11):1191–210. doi: 10.1016/S1473-3099(18)30310-4 30243584; PubMed Central PMCID: PMC6202443.

4. Goritzka M, Makris S, Kausar F, Durant LR, Pereira C, Kumagai Y, et al. Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes. J Exp Med. 2015;212(5):699–714. doi: 10.1084/jem.20140825 25897172; PubMed Central PMCID: PMC4419339.

5. Murawski MR, Bowen GN, Cerny AM, Anderson LJ, Haynes LM, Tripp RA, et al. Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. J Virol. 2009;83(3):1492–500. doi: 10.1128/JVI.00671-08 19019963; PubMed Central PMCID: PMC2620898.

6. Rudd BD, Burstein E, Duckett CS, Li X, Lukacs NW. Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression. J Virol. 2005;79(6):3350–7. doi: 10.1128/JVI.79.6.3350-3357.2005 15731229; PubMed Central PMCID: PMC1075725.

7. Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol. 2000;1(5):398–401. doi: 10.1038/80833 11062499.

8. Haynes LM, Moore DD, Kurt-Jones EA, Finberg RW, Anderson LJ, Tripp RA. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol. 2001;75(22):10730–7. doi: 10.1128/JVI.75.22.10730-10737.2001 11602714; PubMed Central PMCID: PMC114654.

9. Haeberle HA, Takizawa R, Casola A, Brasier AR, Dieterich HJ, Van Rooijen N, et al. Respiratory syncytial virus-induced activation of nuclear factor-kappaB in the lung involves alveolar macrophages and toll-like receptor 4-dependent pathways. J Infect Dis. 2002;186(9):1199–206. doi: 10.1086/344644 12402188.

10. Ehl S, Bischoff R, Ostler T, Vallbracht S, Schulte-Monting J, Poltorak A, et al. The role of Toll-like receptor 4 versus interleukin-12 in immunity to respiratory syncytial virus. Eur J Immunol. 2004;34(4):1146–53. doi: 10.1002/eji.200324449 15048726.

11. Lukacs NW, Smit JJ, Mukherjee S, Morris SB, Nunez G, Lindell DM. Respiratory virus-induced TLR7 activation controls IL-17-associated increased mucus via IL-23 regulation. J Immunol. 2010;185(4):2231–9. doi: 10.4049/jimmunol.1000733 20624950; PubMed Central PMCID: PMC3006454.

12. Bhoj VG, Sun Q, Bhoj EJ, Somers C, Chen X, Torres JP, et al. MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus. Proc Natl Acad Sci U S A. 2008;105(37):14046–51. doi: 10.1073/pnas.0804717105 18780793; PubMed Central PMCID: PMC2532974.

13. Demoor T, Petersen BC, Morris S, Mukherjee S, Ptaschinski C, De Almeida Nagata DE, et al. IPS-1 signaling has a nonredundant role in mediating antiviral responses and the clearance of respiratory syncytial virus. J Immunol. 2012;189(12):5942–53. doi: 10.4049/jimmunol.1201763 23136205; PubMed Central PMCID: PMC3888965.

14. Sasai M, Shingai M, Funami K, Yoneyama M, Fujita T, Matsumoto M, et al. NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type I IFN induction. J Immunol. 2006;177(12):8676–83. doi: 10.4049/jimmunol.177.12.8676 17142768.

15. Loo YM, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L, et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol. 2008;82(1):335–45. doi: 10.1128/JVI.01080-07 17942531; PubMed Central PMCID: PMC2224404.

16. Yoboua F, Martel A, Duval A, Mukawera E, Grandvaux N. Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK beta. J Virol. 2010;84(14):7267–77. doi: 10.1128/JVI.00142-10 20410276; PubMed Central PMCID: PMC2898247.

17. Liu P, Jamaluddin M, Li K, Garofalo RP, Casola A, Brasier AR. Retinoic acid-inducible gene I mediates early antiviral response and Toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells. J Virol. 2007;81(3):1401–11. doi: 10.1128/JVI.01740-06 17108032; PubMed Central PMCID: PMC1797494.

18. Lifland AW, Jung J, Alonas E, Zurla C, Crowe JE Jr., Santangelo PJ. Human respiratory syncytial virus nucleoprotein and inclusion bodies antagonize the innate immune response mediated by MDA5 and MAVS. J Virol. 2012;86(15):8245–58. doi: 10.1128/JVI.00215-12 22623778; PubMed Central PMCID: PMC3421640.

19. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol. 2009;10(10):1073–80. doi: 10.1038/ni.1782 19701189; PubMed Central PMCID: PMC2752345.

20. Thapa RJ, Ingram JP, Ragan KB, Nogusa S, Boyd DF, Benitez AA, et al. DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death. Cell Host Microbe. 2016;20(5):674–81. doi: 10.1016/j.chom.2016.09.014 27746097.

21. Kesavardhana S, Kuriakose T, Guy CS, Samir P, Malireddi RKS, Mishra A, et al. ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death. J Exp Med. 2017;214(8):2217–29. doi: 10.1084/jem.20170550 28634194; PubMed Central PMCID: PMC5551577.

22. Maelfait J, Liverpool L, Bridgeman A, Ragan KB, Upton JW, Rehwinkel J. Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. EMBO J. 2017;36(17):2529–43. doi: 10.15252/embj.201796476 28716805; PubMed Central PMCID: PMC5579359.

23. Hall CB, Douglas RG Jr., Simons RL, Geiman JM. Interferon production in children with respiratory syncytial, influenza, and parainfluenza virus infections. J Pediatr. 1978;93(1):28–32. doi: 10.1016/s0022-3476(78)80594-0 206677.

24. McIntosh K. Interferon in nasal secretions from infants with viral respiratory tract infections. J Pediatr. 1978;93(1):33–6. doi: 10.1016/s0022-3476(78)80595-2 650342.

25. Scagnolari C, Midulla F, Pierangeli A, Moretti C, Bonci E, Berardi R, et al. Gene expression of nucleic acid-sensing pattern recognition receptors in children hospitalized for respiratory syncytial virus-associated acute bronchiolitis. Clin Vaccine Immunol. 2009;16(6):816–23. doi: 10.1128/CVI.00445-08 19386802; PubMed Central PMCID: PMC2691037.

26. Melendi GA, Coviello S, Bhat N, Zea-Hernandez J, Ferolla FM, Polack FP. Breastfeeding is associated with the production of type I interferon in infants infected with influenza virus. Acta Paediatr. 2010;99(10):1517–21. doi: 10.1111/j.1651-2227.2010.01862.x 20456265; PubMed Central PMCID: PMC5454496.

27. Teng MN, Collins PL. Altered growth characteristics of recombinant respiratory syncytial viruses which do not produce NS2 protein. J Virol. 1999;73(1):466–73. 9847352; PubMed Central PMCID: PMC103853.

28. Whitehead SS, Bukreyev A, Teng MN, Firestone CY, St Claire M, Elkins WR, et al. Recombinant respiratory syncytial virus bearing a deletion of either the NS2 or SH gene is attenuated in chimpanzees. J Virol. 1999;73(4):3438–42. 10074199; PubMed Central PMCID: PMC104109.

29. Jin H, Zhou H, Cheng X, Tang R, Munoz M, Nguyen N. Recombinant respiratory syncytial viruses with deletions in the NS1, NS2, SH, and M2-2 genes are attenuated in vitro and in vivo. Virology. 2000;273(1):210–8. doi: 10.1006/viro.2000.0393 10891423.

30. Schlender J, Bossert B, Buchholz U, Conzelmann KK. Bovine respiratory syncytial virus nonstructural proteins NS1 and NS2 cooperatively antagonize alpha/beta interferon-induced antiviral response. J Virol. 2000;74(18):8234–42. doi: 10.1128/jvi.74.18.8234-8242.2000 10954520; PubMed Central PMCID: PMC116331.

31. Teng MN, Whitehead SS, Bermingham A, St Claire M, Elkins WR, Murphy BR, et al. Recombinant respiratory syncytial virus that does not express the NS1 or M2-2 protein is highly attenuated and immunogenic in chimpanzees. J Virol. 2000;74(19):9317–21. doi: 10.1128/jvi.74.19.9317-9321.2000 10982380; PubMed Central PMCID: PMC102132.

32. Spann KM, Tran KC, Chi B, Rabin RL, Collins PL. Suppression of the induction of alpha, beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages [corrected]. J Virol. 2004;78(8):4363–9. doi: 10.1128/JVI.78.8.4363-4369.2004 15047850; PubMed Central PMCID: PMC374276.

33. Valarcher JF, Furze J, Wyld S, Cook R, Conzelmann KK, Taylor G. Role of alpha/beta interferons in the attenuation and immunogenicity of recombinant bovine respiratory syncytial viruses lacking NS proteins. J Virol. 2003;77(15):8426–39. doi: 10.1128/JVI.77.15.8426-8439.2003 12857912; PubMed Central PMCID: PMC165239.

34. Buchholz UJ, Finke S, Conzelmann KK. Generation of bovine respiratory syncytial virus (BRSV) from cDNA: BRSV NS2 is not essential for virus replication in tissue culture, and the human RSV leader region acts as a functional BRSV genome promoter. J Virol. 1999;73(1):251–9. 9847328; PubMed Central PMCID: PMC103829.

35. Wright PF, Karron RA, Madhi SA, Treanor JJ, King JC, O'Shea A, et al. The interferon antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for humans. J Infect Dis. 2006;193(4):573–81. doi: 10.1086/499600 16425137.

36. Luongo C, Winter CC, Collins PL, Buchholz UJ. Respiratory syncytial virus modified by deletions of the NS2 gene and amino acid S1313 of the L polymerase protein is a temperature-sensitive, live-attenuated vaccine candidate that is phenotypically stable at physiological temperature. J Virol. 2013;87(4):1985–96. doi: 10.1128/JVI.02769-12 23236065; PubMed Central PMCID: PMC3571493.

37. Chatterjee S, Luthra P, Esaulova E, Agapov E, Yen BC, Borek DM, et al. Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses. Nat Microbiol. 2017;2:17101. doi: 10.1038/nmicrobiol.2017.101 28665409.

38. Bossert B, Marozin S, Conzelmann KK. Nonstructural proteins NS1 and NS2 of bovine respiratory syncytial virus block activation of interferon regulatory factor 3. J Virol. 2003;77(16):8661–8. doi: 10.1128/JVI.77.16.8661-8668.2003 12885884; PubMed Central PMCID: PMC167228.

39. Ren J, Liu T, Pang L, Li K, Garofalo RP, Casola A, et al. A novel mechanism for the inhibition of interferon regulatory factor-3-dependent gene expression by human respiratory syncytial virus NS1 protein. J Gen Virol. 2011;92(Pt 9):2153–9. doi: 10.1099/vir.0.032987-0 21632562; PubMed Central PMCID: PMC3353388.

40. Tran KC, He B, Teng MN. Replacement of the respiratory syncytial virus nonstructural proteins NS1 and NS2 by the V protein of parainfluenza virus 5. Virology. 2007;368(1):73–82. doi: 10.1016/j.virol.2007.06.017 17632199; PubMed Central PMCID: PMC2078599.

41. Munir S, Le Nouen C, Luongo C, Buchholz UJ, Collins PL, Bukreyev A. Nonstructural proteins 1 and 2 of respiratory syncytial virus suppress maturation of human dendritic cells. J Virol. 2008;82(17):8780–96. doi: 10.1128/JVI.00630-08 18562519; PubMed Central PMCID: PMC2519638.

42. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A. 2005;102(49):17717–22. doi: 10.1073/pnas.0508531102 16301520; PubMed Central PMCID: PMC1308909.

43. Yang Y, Liang Y, Qu L, Chen Z, Yi M, Li K, et al. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc Natl Acad Sci U S A. 2007;104(17):7253–8. doi: 10.1073/pnas.0611506104 17438296; PubMed Central PMCID: PMC1855380.

44. Luthra P, Ramanan P, Mire CE, Weisend C, Tsuda Y, Yen B, et al. Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome. Cell Host Microbe. 2013;14(1):74–84. doi: 10.1016/j.chom.2013.06.010 23870315; PubMed Central PMCID: PMC3875338.

45. Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, et al. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe. 2009;5(5):439–49. doi: 10.1016/j.chom.2009.04.006 19454348; PubMed Central PMCID: PMC2737813.

46. Boyapalle S, Wong T, Garay J, Teng M, San Juan-Vergara H, Mohapatra S, et al. Respiratory syncytial virus NS1 protein colocalizes with mitochondrial antiviral signaling protein MAVS following infection. PLoS ONE. 2012;7(2):e29386. doi: 10.1371/journal.pone.0029386 22383950; PubMed Central PMCID: PMC3288005.

47. Ban J, Lee NR, Lee NJ, Lee JK, Quan FS, Inn KS. Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling. Viruses. 2018;10(12). doi: 10.3390/v10120716 30558248; PubMed Central PMCID: PMC6316657.

48. Hu Y, Li W, Gao T, Cui Y, Jin Y, Li P, et al. The Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Inhibits Type I Interferon Production by Interfering with TRIM25-Mediated RIG-I Ubiquitination. J Virol. 2017;91(8). doi: 10.1128/JVI.02143-16 28148787; PubMed Central PMCID: PMC5375661.

49. Koliopoulos MG, Lethier M, van der Veen AG, Haubrich K, Hennig J, Kowalinski E, et al. Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition. Nat Commun. 2018;9(1):1820. doi: 10.1038/s41467-018-04214-8 29739942; PubMed Central PMCID: PMC5940772.

50. Ling Z, Tran KC, Teng MN. Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J Virol. 2009;83(8):3734–42. doi: 10.1128/JVI.02434-08 19193793; PubMed Central PMCID: PMC2663251.

51. Goswami R, Majumdar T, Dhar J, Chattopadhyay S, Bandyopadhyay SK, Verbovetskaya V, et al. Viral degradasome hijacks mitochondria to suppress innate immunity. Cell Res. 2013;23(8):1025–42. doi: 10.1038/cr.2013.98 23877405; PubMed Central PMCID: PMC3731571.

52. Swedan S, Musiyenko A, Barik S. Respiratory syncytial virus nonstructural proteins decrease levels of multiple members of the cellular interferon pathways. J Virol. 2009;83(19):9682–93. doi: 10.1128/JVI.00715-09 19625398; PubMed Central PMCID: PMC2748017.

53. Deng Y, Yan Y, Tan KS, Liu J, Chow VT, Tao ZZ, et al. MicroRNA-146a induction during influenza H3N2 virus infection targets and regulates TRAF6 levels in human nasal epithelial cells (hNECs). Exp Cell Res. 2017;352(2):184–92. doi: 10.1016/j.yexcr.2017.01.011 28131813.

54. Wu H, Fan H, Shou Z, Xu M, Chen Q, Ai C, et al. Extracellular vesicles containing miR-146a attenuate experimental colitis by targeting TRAF6 and IRAK1. Int Immunopharmacol. 2019;68:204–12. doi: 10.1016/j.intimp.2018.12.043 30654310.

55. Eilam-Frenkel B, Naaman H, Brkic G, Veksler-Lublinsky I, Rall G, Shemer-Avni Y, et al. MicroRNA 146-5p, miR-let-7c-5p, miR-221 and miR-345-5p are differentially expressed in Respiratory Syncytial Virus (RSV) persistently infected HEp-2 cells. Virus Res. 2018;251:34–9. doi: 10.1016/j.virusres.2018.05.006 29733865.

56. Spann KM, Tran KC, Collins PL. Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappaB, and proinflammatory cytokines. J Virol. 2005;79(9):5353–62. doi: 10.1128/JVI.79.9.5353-5362.2005 15827150; PubMed Central PMCID: PMC1082743.

57. Bitko V, Shulyayeva O, Mazumder B, Musiyenko A, Ramaswamy M, Look DC, et al. Nonstructural proteins of respiratory syncytial virus suppress premature apoptosis by an NF-kappaB-dependent, interferon-independent mechanism and facilitate virus growth. J Virol. 2007;81(4):1786–95. doi: 10.1128/JVI.01420-06 17151097; PubMed Central PMCID: PMC1797585.

58. Swedan S, Andrews J, Majumdar T, Musiyenko A, Barik S. Multiple functional domains and complexes of the two nonstructural proteins of human respiratory syncytial virus contribute to interferon suppression and cellular location. J Virol. 2011;85(19):10090–100. doi: 10.1128/JVI.00413-11 21795342; PubMed Central PMCID: PMC3196442.

59. Zhang Y, Yang L, Wang H, Zhang G, Sun X. Respiratory syncytial virus non-structural protein 1 facilitates virus replication through miR-29a-mediated inhibition of interferon-alpha receptor. Biochem Biophys Res Commun. 2016;478(3):1436–41. doi: 10.1016/j.bbrc.2016.08.142 27569280.

60. Ramaswamy M, Shi L, Monick MM, Hunninghake GW, Look DC. Specific inhibition of type I interferon signal transduction by respiratory syncytial virus. Am J Respir Cell Mol Biol. 2004;30(6):893–900. doi: 10.1165/rcmb.2003-0410OC 14722224.

61. Ramaswamy M, Shi L, Varga SM, Barik S, Behlke MA, Look DC. Respiratory syncytial virus nonstructural protein 2 specifically inhibits type I interferon signal transduction. Virology. 2006;344(2):328–39. doi: 10.1016/j.virol.2005.09.009 16216295.

62. Lo MS, Brazas RM, Holtzman MJ. Respiratory syncytial virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon responsiveness. J Virol. 2005;79(14):9315–9. doi: 10.1128/JVI.79.14.9315-9319.2005 15994826; PubMed Central PMCID: PMC1168759.

63. Ren J, Kolli D, Liu T, Xu R, Garofalo RP, Casola A, et al. Human metapneumovirus inhibits IFN-beta signaling by downregulating Jak1 and Tyk2 cellular levels. PLoS ONE. 2011;6(9):e24496. doi: 10.1371/journal.pone.0024496 21949722; PubMed Central PMCID: PMC3176284.

64. Moore EC, Barber J, Tripp RA. Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15). Virol J. 2008;5:116. doi: 10.1186/1743-422X-5-116 18851747; PubMed Central PMCID: PMC2577635.

65. Hashimoto K, Ishibashi K, Ishioka K, Zhao D, Sato M, Ohara S, et al. RSV replication is attenuated by counteracting expression of the suppressor of cytokine signaling (SOCS) molecules. Virology. 2009;391(2):162–70. doi: 10.1016/j.virol.2009.06.026 19595407.

66. Xu X, Zheng J, Zheng K, Hou Y, Zhao F, Zhao D. Respiratory syncytial virus NS1 protein degrades STAT2 by inducing SOCS1 expression. Intervirology. 2014;57(2):65–73. doi: 10.1159/000357327 24480984.

67. Zheng J, Yang P, Tang Y, Pan Z, Zhao D. Respiratory Syncytial Virus Nonstructural Proteins Upregulate SOCS1 and SOCS3 in the Different Manner from Endogenous IFN Signaling. J Immunol Res. 2015;2015:738547. doi: 10.1155/2015/738547 26557722; PubMed Central PMCID: PMC4628668.

68. Nishio M, Tsurudome M, Ito M, Garcin D, Kolakofsky D, Ito Y. Identification of paramyxovirus V protein residues essential for STAT protein degradation and promotion of virus replication. J Virol. 2005;79(13):8591–601. doi: 10.1128/JVI.79.13.8591-8601.2005 15956600; PubMed Central PMCID: PMC1143765.

69. Xu W, Edwards MR, Borek DM, Feagins AR, Mittal A, Alinger JB, et al. Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe. 2014;16(2):187–200. doi: 10.1016/j.chom.2014.07.008 25121748; PubMed Central PMCID: PMC4188415.

70. Sugai A, Sato H, Takayama I, Yoneda M, Kai C. Nipah and Hendra Virus Nucleoproteins Inhibit Nuclear Accumulation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT2 by Interfering with Their Complex Formation. J Virol. 2017;91(21). doi: 10.1128/JVI.01136-17 28835499; PubMed Central PMCID: PMC5640859.

71. Cheon H, Holvey-Bates EG, Schoggins JW, Forster S, Hertzog P, Imanaka N, et al. IFNbeta-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO J. 2013;32(20):2751–63. doi: 10.1038/emboj.2013.203 24065129; PubMed Central PMCID: PMC3801437.

72. Rusinova I, Forster S, Yu S, Kannan A, Masse M, Cumming H, et al. Interferome v2.0: an updated database of annotated interferon-regulated genes. Nucleic Acids Res. 2013;41(Database issue):D1040–6. doi: 10.1093/nar/gks1215 23203888; PubMed Central PMCID: PMC3531205.

73. Elliott J, Lynch OT, Suessmuth Y, Qian P, Boyd CR, Burrows JF, et al. Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase. J Virol. 2007;81(7):3428–36. doi: 10.1128/JVI.02303-06 17251292; PubMed Central PMCID: PMC1866062.

74. Atreya PL, Kulkarni S. Respiratory syncytial virus strain A2 is resistant to the antiviral effects of type I interferons and human MxA. Virology. 1999;261(2):227–41. doi: 10.1006/viro.1999.9835 10497108.

75. Dhar J, Cuevas RA, Goswami R, Zhu J, Sarkar SN, Barik S. 2'-5'-Oligoadenylate Synthetase-Like Protein Inhibits Respiratory Syncytial Virus Replication and Is Targeted by the Viral Nonstructural Protein 1. J Virol. 2015;89(19):10115–9. doi: 10.1128/JVI.01076-15 26178980; PubMed Central PMCID: PMC4577923.

76. Ribaudo M, Barik S. The nonstructural proteins of Pneumoviruses are remarkably distinct in substrate diversity and specificity. Virol J. 2017;14(1):215. doi: 10.1186/s12985-017-0881-7 29110727; PubMed Central PMCID: PMC5674761.

77. Machado D, Pizzorno A, Hoffmann J, Traversier A, Endtz H, Lina B, et al. Role of p53/NF-kappaB functional balance in respiratory syncytial virus-induced inflammation response. J Gen Virol. 2018;99(4):489–500. doi: 10.1099/jgv.0.001040 29504924.

78. Liesman RM, Buchholz UJ, Luongo CL, Yang L, Proia AD, DeVincenzo JP, et al. RSV-encoded NS2 promotes epithelial cell shedding and distal airway obstruction. J Clin Invest. 2014;124(5):2219–33. doi: 10.1172/JCI72948 24713657; PubMed Central PMCID: PMC4001550.

79. Buckingham SC, Jafri HS, Bush AJ, Carubelli CM, Sheeran P, Hardy RD, et al. A randomized, double-blind, placebo-controlled trial of dexamethasone in severe respiratory syncytial virus (RSV) infection: effects on RSV quantity and clinical outcome. J Infect Dis. 2002;185(9):1222–8. doi: 10.1086/340024 12001038.

80. Ermers MJ, Rovers MM, van Woensel JB, Kimpen JL, Bont LJ, Group RSVCS. The effect of high dose inhaled corticosteroids on wheeze in infants after respiratory syncytial virus infection: randomised double blind placebo controlled trial. BMJ. 2009;338:b897. doi: 10.1136/bmj.b897 19336497; PubMed Central PMCID: PMC2663654.

81. Somers CC, Ahmad N, Mejias A, Buckingham SC, Carubelli C, Katz K, et al. Effect of dexamethasone on respiratory syncytial virus-induced lung inflammation in children: results of a randomized, placebo controlled clinical trial. Pediatr Allergy Immunol. 2009;20(5):477–85. doi: 10.1111/j.1399-3038.2009.00852.x 19397752.

82. Bonville CA, Mehta PA, Krilov LR, Rosenberg HF, Domachowske JB. Epithelial cells infected with respiratory syncytial virus are resistant to the anti-inflammatory effects of hydrocortisone. Cell Immunol. 2001;213(2):134–40. doi: 10.1006/cimm.2001.1869 11831875.

83. Hinzey A, Alexander J, Corry J, Adams KM, Claggett AM, Traylor ZP, et al. Respiratory syncytial virus represses glucocorticoid receptor-mediated gene activation. Endocrinology. 2011;152(2):483–94. doi: 10.1210/en.2010-0774 21190962; PubMed Central PMCID: PMC3037158.

84. Webster Marketon JI, Corry J. Respiratory syncytial virus (RSV) suppression of glucocorticoid receptor phosphorylation does not account for repression of transactivation. FEBS Open Bio. 2013;3:305–9. doi: 10.1016/j.fob.2013.07.005 23951552; PubMed Central PMCID: PMC3741917.

85. Webster Marketon JI, Corry J. Poly I:C and respiratory syncytial virus (RSV) inhibit glucocorticoid receptor (GR)-mediated transactivation in lung epithelial, but not monocytic, cell lines. Virus Res. 2013;176(1–2):303–6. doi: 10.1016/j.virusres.2013.06.011 23830998.

86. Webster Marketon JI, Corry J, Teng MN. The respiratory syncytial virus (RSV) nonstructural proteins mediate RSV suppression of glucocorticoid receptor transactivation. Virology. 2014;449:62–9. doi: 10.1016/j.virol.2013.11.014 24418538; PubMed Central PMCID: PMC3904736.

87. Xia YC, Radwan A, Keenan CR, Langenbach SY, Li M, Radojicic D, et al. Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-beta Activity. PLoS Pathog. 2017;13(1):e1006138. doi: 10.1371/journal.ppat.1006138 28046097; PubMed Central PMCID: PMC5234851.

88. Xie J, Long X, Gao L, Chen S, Zhao K, Li W, et al. Respiratory Syncytial Virus Nonstructural Protein 1 Blocks Glucocorticoid Receptor Nuclear Translocation by Targeting IPO13 and May Account for Glucocorticoid Insensitivity. J Infect Dis. 2017;217(1):35–46. doi: 10.1093/infdis/jix445 28968829.

89. Bakre A, Wu W, Hiscox J, Spann K, Teng MN, Tripp RA. Human respiratory syncytial virus non-structural protein NS1 modifies miR-24 expression via transforming growth factor-beta. J Gen Virol. 2015;96(11):3179–91. doi: 10.1099/jgv.0.000261 26253191; PubMed Central PMCID: PMC4806578.

90. Thornburg NJ, Hayward SL, Crowe JE Jr. Respiratory syncytial virus regulates human microRNAs by using mechanisms involving beta interferon and NF-kappaB. MBio. 2012;3(6). doi: 10.1128/mBio.00220-12 23249809; PubMed Central PMCID: PMC3529541.

91. Bakre A, Mitchell P, Coleman JK, Jones LP, Saavedra G, Teng M, et al. Respiratory syncytial virus modifies microRNAs regulating host genes that affect virus replication. J Gen Virol. 2012;93(Pt 11):2346–56. doi: 10.1099/vir.0.044255-0 22894925; PubMed Central PMCID: PMC3542124.

92. Zhou R, Hu G, Liu J, Gong AY, Drescher KM, Chen XM. NF-kappaB p65-dependent transactivation of miRNA genes following Cryptosporidium parvum infection stimulates epithelial cell immune responses. PLoS Pathog. 2009;5(12):e1000681. doi: 10.1371/journal.ppat.1000681 19997496; PubMed Central PMCID: PMC2778997.

93. Johnson TR, Johnson CN, Corbett KS, Edwards GC, Graham BS. Primary human mDC1, mDC2, and pDC dendritic cells are differentially infected and activated by respiratory syncytial virus. PLoS ONE. 2011;6(1):e16458. doi: 10.1371/journal.pone.0016458 21297989; PubMed Central PMCID: PMC3030580.

94. Munir S, Hillyer P, Le Nouen C, Buchholz UJ, Rabin RL, Collins PL, et al. Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response. PLoS Pathog. 2011;7(4):e1001336. doi: 10.1371/journal.ppat.1001336 21533073; PubMed Central PMCID: PMC3080852.

95. Kotelkin A, Belyakov IM, Yang L, Berzofsky JA, Collins PL, Bukreyev A. The NS2 protein of human respiratory syncytial virus suppresses the cytotoxic T-cell response as a consequence of suppressing the type I interferon response. J Virol. 2006;80(12):5958–67. doi: 10.1128/JVI.00181-06 16731934; PubMed Central PMCID: PMC1472589.

96. Qi F, Wang D, Liu J, Zeng S, Xu L, Hu H, et al. Respiratory macrophages and dendritic cells mediate respiratory syncytial virus-induced IL-33 production in TLR3- or TLR7-dependent manner. Int Immunopharmacol. 2015;29(2):408–15. doi: 10.1016/j.intimp.2015.10.022 26603638.

97. Whelan JN, Tran KC, van Rossum DB, Teng MN. Identification of Respiratory Syncytial Virus Nonstructural Protein 2 Residues Essential for Exploitation of the Host Ubiquitin System and Inhibition of Innate Immune Responses. J Virol. 2016;90(14):6453–63. doi: 10.1128/JVI.00423-16 27147743; PubMed Central PMCID: PMC4936147.

98. Straub CP, Lau WH, Preston FM, Headlam MJ, Gorman JJ, Collins PL, et al. Mutation of the elongin C binding domain of human respiratory syncytial virus non-structural protein 1 (NS1) results in degradation of NS1 and attenuation of the virus. Virol J. 2011;8:252. doi: 10.1186/1743-422X-8-252 21600055; PubMed Central PMCID: PMC3121706.

99. Zhang W, Yang H, Kong X, Mohapatra S, San Juan-Vergara H, Hellermann G, et al. Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med. 2005;11(1):56–62. doi: 10.1038/nm1174 15619625.

100. Vasou A, Paulus C, Narloch J, Gage ZO, Rameix-Welti MA, Eleouet JF, et al. Modular cell-based platform for high throughput identification of compounds that inhibit a viral interferon antagonist of choice. Antiviral Res. 2018;150:79–92. doi: 10.1016/j.antiviral.2017.10.012 29037975; PubMed Central PMCID: PMC5800491.