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The influence of commensal bacteria on infection with enteric viruses

Nature Reviews Microbiology volume 14, pages 197–204 (2016)Cite this article

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Abstract

The intestinal microbiota exerts a marked influence in the mammalian host, both during homeostasis and disease. However, until very recently, there has been relatively little focus on the potential effect of commensal microorganisms on viral infection of the intestinal tract. In this Progress article, I review the recent advances that elucidate the mechanisms by which enteric viruses use commensal bacteria to enhance viral infectivity. These mechanisms segregate into two general categories: the direct facilitation of viral infection, including bacterial stabilization of viral particles and the facilitation of viral attachment to host target cells; and the indirect skewing of the antiviral immune response in a manner that promotes viral infection. Finally, I discuss the implications of these interactions for the development of vaccines and novel therapeutic approaches.

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Figure 1: Enteric virus interactions with bacterial surface glycans can facilitate viral stability and binding to target cells.
Figure 2: Commensal bacteria can induce a tolerogenic microenvironment that facilitates the establishment of MMTV persistence.
Figure 3: Commensal bacteria can suppress the type III interferon response, facilitating the establishment of murine norovirus persistence.

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References

  1. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Norman, J. M., Handley, S. A. & Virgin, H. W. Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities. Gastroenterology 146, 1459–1469 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sommer, F. & Bäckhed, F. The gut microbiota — masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Nicholson, J. K. et al. Host–gut microbiota metabolic interactions. Science 336, 1262–1267 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Tremaroli, V. & Bäckhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kamada, N. & Núñez, G. Regulation of the immune system by the resident intestinal bacteria. Gastroenterology 146, 1477–1488 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat. Immunol. 4, 269–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Tate, J. E. et al. 2008 estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect. Dis. 12, 136–141 (2012).

    Article  PubMed  Google Scholar 

  13. Lanata, C. F. et al. Global causes of diarrheal disease mortality in children<5 years of age: a systematic review. PLoS ONE 8, e72788 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Payne, D. C. et al. Norovirus and medically attended gastroenteritis in U.S. children. N. Engl. J. Med. 368, 1121–1130 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Koo, H. L. et al. Noroviruses: the most common pediatric viral enteric pathogen at a large university hospital after introduction of rotavirus vaccination. J. Pediatr. Infect. Dis. Soc. 2, 57–60 (2013).

    Article  Google Scholar 

  16. Koo, H. L., Ajami, N., Atmar, R. L. & DuPont, H. L. Noroviruses: the leading cause of foodborne disease worldwide. Discov. Med. 10, 61–70 (2010).

    PubMed  PubMed Central  Google Scholar 

  17. Ahmed, S. M. et al. Global prevalence of norovirus in cases of gastroenteritis: a systematic review and meta-analysis. Lancet Infect. Dis. 14, 725–730 (2014).

    Article  PubMed  Google Scholar 

  18. Bosch, A., Pintó, R. M. & Guix, S. Human astroviruses. Clin. Microbiol. Rev. 27, 1048–1074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ross, S. R. Mouse mammary tumor virus molecular biology and oncogenesis. Viruses 2, 2000–2012 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kuss, S. K. et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334, 249–252 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kane, M. et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334, 245–249 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Uchiyama, R., Chassaing, B., Zhang, B. & Gewirtz, A. T. Antibiotic treatment suppresses rotavirus infection and enhances specific humoral immunity. J. Infect. Dis. 210, 171–182 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jones, M. K. et al. Enteric bacteria promote human and murine norovirus infection of B cells. Science 346, 755–759 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94–98 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Baldridge, M. T. et al. Commensal microbes and interferon-λ determine persistence of enteric murine norovirus infection. Science 347, 266–269 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Robinson, C. M., Jesudhasan, P. R. & Pfeiffer, J. K. Bacterial lipopolysaccharide binding enhances virion stability and promotes environmental fitness of an enteric virus. Cell Host Microbe 15, 36–46 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tan, M. & Jiang, X. Norovirus and its histo-blood group antigen receptors: an answer to a historical puzzle. Trends Microbiol. 13, 285–293 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Miura, T. et al. Histo-blood group antigen-like substances of human enteric bacteria as specific adsorbents for human noroviruses. J. Virol. 87, 9441–9451 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Karst, S. M. Identification of a novel cellular target and a co-factor for norovirus infection – B cells and commensal bacteria. Gut Microbes 6, 266–271 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat. Rev. Immunol. 10, 131–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Mukherji, A., Kobiita, A., Ye, T. & Chambon, P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153, 812–827 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 10, 1969–1980 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Thornton, A. M. & Shevach, E. M. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J. Immunol. 164, 183–190 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. & Yamaguchi, T. Regulatory T cells: how do they suppress immune responses? Int. Immunol. 21, 1105–1111 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Caridade, M., Graca, L. & Ribeiro, R. M. Mechanisms underlying CD4+ Treg immune regulation in the adult: from experiments to models. Front. Immunol. 4, 378 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Jude, B. A. et al. Subversion of the innate immune system by a retrovirus. Nat. Immunol. 4, 573–578 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Wilks, J. et al. Mammalian lipopolysaccharide receptors incorporated into the retroviral envelope augment virus transmission. Cell Host Microbe 18, 456–462 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Blacklow, N. R. et al. Acute infectious nonbacterial gastroenteritis: etiology and pathogenesis. Ann. Intern. Med. 76, 993–1008 (1972).

    Article  Google Scholar 

  39. Dolin, R., Levy, A. G., Wyatt, R. G., Thornhill, T. S. & Gardner, J. D. Viral gastroenteritis induced by the Hawaii agent. Jejunal histopathology and serologic response. Am. J. Med. 59, 761–768 (1975).

    Article  CAS  PubMed  Google Scholar 

  40. Schreiber, D. S., Blacklow, N. R. & Trier, J. S. The mucosal lesion of the proximal small intestine in acute infectious nonbacterial gastroenteritis. N. Engl. J. Med. 288, 1318–1323 (1973).

    Article  CAS  PubMed  Google Scholar 

  41. Mumphrey, S. M. et al. Murine norovirus 1 infection is associated with histopathological changes in immunocompetent hosts, but clinical disease is prevented by STAT1-dependent interferon responses. J. Virol. 81, 3251–3263 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Souza, M., Azevedo, M. S. P., Jung, K., Cheetham, S. & Saif, L. J. Pathogenesis and immune responses in gnotobiotic calves after infection with the genogroup II.4-HS66 strain of human norovirus. J. Virol. 82, 1777–1786 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Troeger, H. et al. Structural and functional changes of the duodenum in human norovirus infection. Gut 58, 1070–1077 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Kahan, S. M. et al. Comparative murine norovirus studies reveal a lack of correlation between intestinal virus titers and enteric pathology. Virology 421, 202–210 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Basic, M. et al. Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice. Inflamm. Bowel Dis. 20, 431–443 (2014).

    Article  PubMed  Google Scholar 

  46. Nice, T. J. et al. Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity. Science 347, 269–273 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Wobus, C. E. et al. Replication of norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol. 2, e432 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Bok, K. et al. Chimpanzees as an animal model for human norovirus infection and vaccine development. Proc. Natl Acad. Sci. USA 108, 325–330 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Duizer, E. et al. Laboratory efforts to cultivate noroviruses. J. Gen. Virol. 85, 79–87 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Pott, J. et al. IFN-λ determines the intestinal epithelial antiviral host defense. Proc. Natl Acad. Sci. USA 108, 7944–7949 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Zhang, B. et al. Prevention and cure of rotavirus infection via TLR5/NLRC4–mediated production of IL-22 and IL-18. Science 346, 861–865 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Johansson, M. E. V. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Blumershine, R. V. & Savage, D. C. Filamentous microbes indigenous to the murine small bowel: a scanning electron microscopic study of their morphology and attachment to the epithelium. Microb. Ecol. 4, 95–103 (1977).

    Article  CAS  PubMed  Google Scholar 

  54. Klaasen, H. L. B. M., Koopman, J. P., Poelma, F. G. J. & Beynen, A. C. Intestinal, segmented, filamentous bacteria. FEMS Microbiol. Rev. 8, 165–179 (1992).

    Article  CAS  PubMed  Google Scholar 

  55. Kaparakis-Liaskos, M. & Ferrero, R. L. Immune modulation by bacterial outer membrane vesicles. Nat. Rev. Immunol. 15, 375–387 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Schwechheimer, C. & Kuehn, M. J. Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat. Rev. Microbiol. 13, 605–619 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mabbott, N. A., Donaldson, D. S., Ohno, H., Williams, I. R. & Mahajan, A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 6, 666–677 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Golovkina, T. V., Shlomchik, M., Hannum, L. & Chervonsky, A. Organogenic role of B lymphocytes in mucosal immunity. Science 286, 1965–1968 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Gonzalez-Hernandez, M. B. et al. Murine norovirus transcytosis across an in vitro polarized murine intestinal epithelial monolayer is mediated by M-like cells. J. Virol. 87, 12685–12693 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gonzalez-Hernandez, M. B. et al. Efficient norovirus and reovirus replication in the mouse intestine requires microfold (M) cells. J. Virol. 88, 6934–6943 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sicin´ski, P. et al. Poliovirus type 1 enters the human host through intestinal M cells. Gastroenterology 98, 56–58 (1990).

    Article  Google Scholar 

  62. Wolf, J. L. et al. Intestinal M cells: a pathway for entry of reovirus into the host. Science 212, 471–472 (1981).

    Article  CAS  PubMed  Google Scholar 

  63. Marionneau, S. et al. Norwalk virus binds to histo-blood group antigens present on gastroduodenal epithelial cells of secretor individuals. Gastroenterology 122, 1967–1977 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Tamura, M., Natori, K., Kobayashi, M., Miyamura, T. & Takeda, N. Interaction of recombinant norwalk virus particles with the 105-kilodalton cellular binding protein, a candidate receptor molecule for virus attachment. J. Virol. 74, 11589–11597 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. White, L. J. et al. Attachment and entry of recombinant norwalk virus capsids to cultured human and animal cell lines. J. Virol. 70, 6589–6597 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH; grant R01AI116892).

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  1. Department of Molecular Genetics & Microbiology, College of Medicine, Emerging Pathogens Institute, University of Florida, Gainesville, 32608, Florida, USA

    Stephanie M. Karst

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Correspondence to Stephanie M. Karst.

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Karst, S. The influence of commensal bacteria on infection with enteric viruses. Nat Rev Microbiol 14, 197–204 (2016). https://doi.org/10.1038/nrmicro.2015.25

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