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Journal of General Virology header logo Journal of General Virology

Volume 105, Issue 2

Latent gammaherpesvirus infection enhances type I IFN response and reduces virus spread in an influenza A virus co-infection model Open Access

Abstract

Infections with persistent or latent viruses alter host immune homeostasis and have potential to affect the outcome of concomitant acute viral infections such as influenza A virus (IAV). Gammaherpesviruses establish life-long infections and require an on-going immune response to control reactivation. We have used a murine model of co-infection to investigate the response to IAV infection in mice latently infected with the gammaherpesvirus MHV-68. Over the course of infection, latently infected BALB/c mice showed less weight loss, clinical signs, pulmonary cellular infiltration and expression of inflammatory mediators than naïve mice infected with IAV and had significantly more activated CD8 T cells in the lungs. Four days after IAV infection, virus spread in the lungs of latently infected animals was significantly lower than in naïve animals. By 7 days after IAV infection latently infected lungs express elevated levels of cytokines and chemokines indicating they are primed to respond to the secondary infection. Investigation at an early time point showed that 24 h after IAV infection co-infected animals had higher expression of IFNβ and Ddx58 (RIG-I) and a range of ISGs than mice infected with IAV alone suggesting that the type I IFN response plays a role in the protective effect. This effect was mouse strain dependent and did not occur in 129/Sv/Ev mice. These results offer insight into innate immune mechanisms that could be utilized to protect against IAV infection and highlight on-going and persistent viral infections as a significant factor impacting the severity of acute respiratory infections.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): co-infections , heterologous protection , innate immune response and ISGs
Funding
This study was supported by the:
  • Biotechnology and Biological Sciences Research Council (Award BB/J004324/1)
    • Principle Award Recipient: BernadetteM Dutia
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2024-02-08
2025-04-19
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References

  1. Pica N, Bouvier NM. Environmental factors affecting the transmission of respiratory viruses. Curr Opin Virol 2012; 2:90–95 [View Article] [PubMed]
     [Google Scholar]
  2. Horby P, Nguyen NY, Dunstan SJ, Baillie JK, Loeb MB. The role of host genetics in susceptibility to influenza: a systematic review. PLoS One 2012; 7:e33180 [View Article]
     [Google Scholar]
  3. Thompson WW, Comanor L, Shay DK. Epidemiology of seasonal influenza: use of surveillance data and statistical models to estimate the burden of disease. J Infect Dis 2006; 194:S82–S91 [View Article]
     [Google Scholar]
  4. White DW, Suzanne Beard R, Barton ES. Immune modulation during latent herpesvirus infection. Immunol Rev 2012; 245:189–208 [View Article] [PubMed]
     [Google Scholar]
  5. Tanoue T, Umesaki Y, Honda K. Immune responses to gut microbiota-commensals and pathogens. Gut Microbes 2010; 1:224–233 [View Article] [PubMed]
     [Google Scholar]
  6. Kane M, Golovkina T. Common threads in persistent viral infections. J Virol 2010; 84:4116–4123 [View Article] [PubMed]
     [Google Scholar]
  7. Kim E-H, Nguyen T-Q, Casel MAB, Rollon R, Kim S-M et al. Coinfection with SARS-CoV-2 and influenza A virus increases disease severity and impairs neutralizing antibody and CD4+ T cell responses. J Virol 2022; 96:e0187321 [View Article] [PubMed]
     [Google Scholar]
  8. Li H, Zhao X, Zhao Y, Li J, Zheng H et al. H1N1 exposure during the convalescent stage of SARS-CoV-2 infection results in enhanced lung pathologic damage in hACE2 transgenic mice. Emerg Microbes Infect 2021; 10:1156–1168 [View Article] [PubMed]
     [Google Scholar]
  9. Saito F, Ito T, Connett JM, Schaller MA, Carson WF 4th et al. MHV68 latency modulates the host immune response to influenza A virus. Inflammation 2013; 36:1295–1303 [View Article] [PubMed]
     [Google Scholar]
  10. Furman D, Jojic V, Sharma S, Shen-Orr SS, Angel CJL et al. Cytomegalovirus infection enhances the immune response to influenza. Sci Transl Med 2015; 7:281ra43 [View Article] [PubMed]
     [Google Scholar]
  11. Hardisty GR, Knipper JA, Fulton A, Hopkins J, Dutia BM et al. Concurrent infection with the filarial helminth Litomosoides sigmodontis attenuates or worsens influenza A virus pathogenesis in a stage-dependent manner. Front Immunol 2021; 12:819560 [View Article] [PubMed]
     [Google Scholar]
  12. Souquette A, Thomas PG. Past life and future effects-how heterologous infections alter immunity to influenza viruses. Front Immunol 2018; 9:1071 [View Article] [PubMed]
     [Google Scholar]
  13. Collins-McMillen D, Goodrum FD. The loss of binary: pushing the herpesvirus latency paradigm. Curr Clin Microbiol Rep 2017; 4:124–131 [View Article] [PubMed]
     [Google Scholar]
  14. Tronstein E, Johnston C, Huang M-L, Selke S, Magaret A et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA 2011; 305:1441–1449 [View Article] [PubMed]
     [Google Scholar]
  15. Hadinoto V, Shapiro M, Sun CC, Thorley-Lawson DA. The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathog 2009; 5:e1000496 [View Article] [PubMed]
     [Google Scholar]
  16. Russell TA, Tscharke DC. Lytic promoters express protein during herpes simplex virus latency. PLoS Pathog 2016; 12:e1005729 [View Article] [PubMed]
     [Google Scholar]
  17. Ma JZ, Russell TA, Spelman T, Carbone FR, Tscharke DC. Lytic gene expression is frequent in HSV-1 latent infection and correlates with the engagement of a cell-intrinsic transcriptional response. PLoS Pathog 2014; 10:e1004237 [View Article] [PubMed]
     [Google Scholar]
  18. Welsh RM, Che JW, Brehm MA, Selin LK. Heterologous immunity between viruses. Immunol Rev 2010; 235:244–266 [View Article] [PubMed]
     [Google Scholar]
  19. Selin LK, Varga SM, Wong IC, Welsh RM. Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J Exp Med 1998; 188:1705–1715 [View Article] [PubMed]
     [Google Scholar]
  20. Nash AA, Dutia BM, Stewart JP, Davison AJ. Natural history of murine gamma-herpesvirus infection. Philos Trans R Soc Lond B Biol Sci 2001; 356:569–579 [View Article] [PubMed]
     [Google Scholar]
  21. Steed AL, Barton ES, Tibbetts SA, Popkin DL, Lutzke ML et al. Gamma interferon blocks gammaherpesvirus reactivation from latency. J Virol 2006; 80:192–200 [View Article] [PubMed]
     [Google Scholar]
  22. Dutia BM, Clarke CJ, Allen DJ, Nash AA. Pathological changes in the spleens of gamma interferon receptor-deficient mice infected with murine gammaherpesvirus: a role for CD8 T cells. J Virol 1997; 71:4278–4283 [View Article] [PubMed]
     [Google Scholar]
  23. Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 2007; 447:326–329 [View Article] [PubMed]
     [Google Scholar]
  24. Yager EJ, Szaba FM, Kummer LW, Lanzer KG, Burkum CE et al. gamma-herpesvirus-induced protection against bacterial infection is transient. Viral Immunol 2009; 22:67–72 [View Article] [PubMed]
     [Google Scholar]
  25. Nguyen Y, McGuffie BA, Anderson VE, Weinberg JB. Gammaherpesvirus modulation of mouse adenovirus type 1 pathogenesis. Virology 2008; 380:182–190 [View Article] [PubMed]
     [Google Scholar]
  26. Haque A, Rachinel N, Quddus MR, Haque S, Kasper LH et al. Co-infection of malaria and gamma-herpesvirus: exacerbated lung inflammation or cross-protection depends on the stage of viral infection. Clin Exp Immunol 2004; 138:396–404 [View Article] [PubMed]
     [Google Scholar]
  27. Blaskovic D, Stanceková M, Svobodová J, Mistríková J. Isolation of five strains of herpesviruses from two species of free living small rodents. Acta Virol 1980; 24:468 [PubMed]
     [Google Scholar]
  28. Sunil-Chandra NP, Efstathiou S, Arno J, Nash AA. Virological and pathological features of mice infected with murine gamma-herpesvirus 68. J Gen Virol 1992; 73 (Pt 9):2347–2356 [View Article] [PubMed]
     [Google Scholar]
  29. Nicol MQ, Ligertwood Y, Bacon MN, Dutia BM, Nash AA. A novel family of peptides with potent activity against influenza A viruses. J Gen Virol 2012; 93:980–986 [View Article] [PubMed]
     [Google Scholar]
  30. Dutia BM, Reid SJ, Drummond DD, Ligertwood Y, Bennet I et al. A novel cre recombinase imaging system for tracking lymphotropic virus infection in vivo. PLoS One 2009; 4:e6492 [View Article] [PubMed]
     [Google Scholar]
  31. Team, R.C A Language and Environment for Statistical Computing Vienna, Austria: R Foundation for Statistical Computing; 2017
     [Google Scholar]
  32. Ram K, Wickman H. Wesanderson: A Wes Anderson Palette Generator R package version 0.3.2; 2015
     [Google Scholar]
  33. Hothorn T, Bretz F, Westfall P. Simultaneous inference in general parametric models. Biom J 2008; 50:346–363 [View Article] [PubMed]
     [Google Scholar]
  34. Stewart JP, Usherwood EJ, Ross A, Dyson H, Nash T. Lung epithelial cells are a major site of murine gammaherpesvirus persistence. J Exp Med 1998; 187:1941–1951 [View Article] [PubMed]
     [Google Scholar]
  35. Korteweg C, Gu J. Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. Am J Pathol 2008; 172:1155–1170 [View Article] [PubMed]
     [Google Scholar]
  36. Kobasa D, Takada A, Shinya K, Hatta M, Halfmann P et al. Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature 2004; 431:703–707 [View Article] [PubMed]
     [Google Scholar]
  37. Peiris JSM, Hui KPY, Yen H-L. Host response to influenza virus: protection versus immunopathology. Curr Opin Immunol 2010; 22:475–481 [View Article] [PubMed]
     [Google Scholar]
  38. Bermejo-Martin JF, Ortiz de Lejarazu R, Pumarola T, Rello J, Almansa R et al. Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza. Crit Care 2009; 13:R201 [View Article] [PubMed]
     [Google Scholar]
  39. Pichlmair A, Schulz O, Tan CP, Näslund TI, Liljeström P et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 2006; 314:997–1001 [View Article]
     [Google Scholar]
  40. Loo Y-M, Fornek J, Crochet N, Bajwa G, Perwitasari O et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol 2008; 82:335–345 [View Article] [PubMed]
     [Google Scholar]
  41. Culley FJ, Pennycook AMJ, Tregoning JS, Dodd JS, Walzl G et al. Role of CCL5 (RANTES) in viral lung disease. J Virol 2006; 80:8151–8157 [View Article] [PubMed]
     [Google Scholar]
  42. Groom JR, Luster AD. CXCR3 in T cell function. Exp Cell Res 2011; 317:620–631 [View Article] [PubMed]
     [Google Scholar]
  43. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008; 8:533–544 [View Article] [PubMed]
     [Google Scholar]
  44. Cruikshank W, Little F. lnterleukin-16: the ins and outs of regulating T-cell activation. Crit Rev Immunol 2008; 28:467–483 [View Article] [PubMed]
     [Google Scholar]
  45. Cox MA, Barnum SR, Bullard DC, Zajac AJ. ICAM-1-dependent tuning of memory CD8 T-cell responses following acute infection. Proc Natl Acad Sci U S A 2013; 110:1416–1421 [View Article] [PubMed]
     [Google Scholar]
  46. Shi Y, Liu CH, Roberts AI, Das J, Xu G et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don’T know. Cell Res 2006; 16:126–133 [View Article] [PubMed]
     [Google Scholar]
  47. Srivastava B, Błazejewska P, Hessmann M, Bruder D, Geffers R et al. Host genetic background strongly influences the response to influenza a virus infections. PLoS One 2009; 4:e4857 [View Article] [PubMed]
     [Google Scholar]
  48. Trammell RA, Liberati TA, Toth LA. Host genetic background and the innate inflammatory response of lung to influenza virus. Microbes Infect 2012; 14:50–58 [View Article] [PubMed]
     [Google Scholar]
  49. Boon ACM, deBeauchamp J, Hollmann A, Luke J, Kotb M et al. Host genetic variation affects resistance to infection with a highly pathogenic H5N1 influenza A virus in mice. J Virol 2009; 83:10417–10426 [View Article] [PubMed]
     [Google Scholar]
  50. Perrone LA, Plowden JK, García-Sastre A, Katz JM, Tumpey TM. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog 2008; 4:e1000115 [View Article] [PubMed]
     [Google Scholar]
  51. Meliopoulos VA, Van de Velde L-A, Van de Velde NC, Karlsson EA, Neale G et al. An epithelial integrin regulates the amplitude of protective lung interferon responses against multiple respiratory pathogens. PLoS Pathog 2016; 12:e1005804 [View Article] [PubMed]
     [Google Scholar]
  52. Meliopoulos V, Livingston B, Van de Velde L-A, Honce R, Schultz-Cherry S. Absence of β6 integrin reduces influenza disease severity in highly susceptible obese Mice. J Virol 2019; 93:e01646-18 [View Article] [PubMed]
     [Google Scholar]
  53. Kumagai Y, Takeuchi O, Kato H, Kumar H, Matsui K et al. Alveolar macrophages are the primary interferon-alpha producer in pulmonary infection with RNA viruses. Immunity 2007; 27:240–252 [View Article] [PubMed]
     [Google Scholar]
  54. Cornberg M, Clute SC, Watkin LB, Saccoccio FM, Kim S-K et al. CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections. J Immunol 2010; 184:2825–2838 [View Article] [PubMed]
     [Google Scholar]
  55. Zhou K, Wang J, Li A, Zhao W, Wang D et al. Swift and strong NK cell responses protect 129 mice against high-dose influenza virus infection. J Immunol 2016; 196:1842–1854 [View Article]
     [Google Scholar]
  56. Pulit-Penaloza JA, Scherbik SV, Brinton MA. Type 1 IFN-independent activation of a subset of interferon stimulated genes in West Nile virus Eg101-infected mouse cells. Virology 2012; 425:82–94 [View Article] [PubMed]
     [Google Scholar]
  57. Coch C, Stümpel JP, Lilien-Waldau V, Wohlleber D, Kümmerer BM et al. RIG-I activation protects and rescues from lethal influenza virus infection and bacterial superinfection. Mol Ther 2017; 25:2093–2103 [View Article] [PubMed]
     [Google Scholar]
  58. Pizzolla A, Smith JM, Brooks AG, Reading PC. Pattern recognition receptor immunomodulation of innate immunity as a strategy to limit the impact of influenza virus. J Leukoc Biol 2017; 101:851–861 [View Article] [PubMed]
     [Google Scholar]
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Latent gammaherpesvirus infection enhances type I IFN response and reduces virus spread in an influenza A virus co-infection model
J. Gen. Virol. 105, 001962 (2024); https://doi.org/10.1099/jgv.0.001962
/content/journal/jgv/10.1099/jgv.0.001962
/content/journal/jgv/10.1099/jgv.0.001962
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