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.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
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).
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).
Sommer, F. & Bäckhed, F. The gut microbiota — masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).
Nicholson, J. K. et al. Host–gut microbiota metabolic interactions. Science 336, 1262–1267 (2012).
Tremaroli, V. & Bäckhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).
Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).
Kamada, N. & Núñez, G. Regulation of the immune system by the resident intestinal bacteria. Gastroenterology 146, 1477–1488 (2014).
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).
Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011).
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).
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).
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).
Payne, D. C. et al. Norovirus and medically attended gastroenteritis in U.S. children. N. Engl. J. Med. 368, 1121–1130 (2013).
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).
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).
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).
Bosch, A., Pintó, R. M. & Guix, S. Human astroviruses. Clin. Microbiol. Rev. 27, 1048–1074 (2014).
Ross, S. R. Mouse mammary tumor virus molecular biology and oncogenesis. Viruses 2, 2000–2012 (2010).
Kuss, S. K. et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334, 249–252 (2011).
Kane, M. et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334, 245–249 (2011).
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).
Jones, M. K. et al. Enteric bacteria promote human and murine norovirus infection of B cells. Science 346, 755–759 (2014).
Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94–98 (2014).
Baldridge, M. T. et al. Commensal microbes and interferon-λ determine persistence of enteric murine norovirus infection. Science 347, 266–269 (2015).
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).
Tan, M. & Jiang, X. Norovirus and its histo-blood group antigen receptors: an answer to a historical puzzle. Trends Microbiol. 13, 285–293 (2005).
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).
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).
Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat. Rev. Immunol. 10, 131–144 (2010).
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).
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).
Thornton, A. M. & Shevach, E. M. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J. Immunol. 164, 183–190 (2000).
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).
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).
Jude, B. A. et al. Subversion of the innate immune system by a retrovirus. Nat. Immunol. 4, 573–578 (2003).
Wilks, J. et al. Mammalian lipopolysaccharide receptors incorporated into the retroviral envelope augment virus transmission. Cell Host Microbe 18, 456–462 (2015).
Blacklow, N. R. et al. Acute infectious nonbacterial gastroenteritis: etiology and pathogenesis. Ann. Intern. Med. 76, 993–1008 (1972).
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).
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).
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).
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).
Troeger, H. et al. Structural and functional changes of the duodenum in human norovirus infection. Gut 58, 1070–1077 (2009).
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).
Basic, M. et al. Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice. Inflamm. Bowel Dis. 20, 431–443 (2014).
Nice, T. J. et al. Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity. Science 347, 269–273 (2015).
Wobus, C. E. et al. Replication of norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol. 2, e432 (2004).
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).
Duizer, E. et al. Laboratory efforts to cultivate noroviruses. J. Gen. Virol. 85, 79–87 (2004).
Pott, J. et al. IFN-λ determines the intestinal epithelial antiviral host defense. Proc. Natl Acad. Sci. USA 108, 7944–7949 (2011).
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).
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).
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).
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).
Kaparakis-Liaskos, M. & Ferrero, R. L. Immune modulation by bacterial outer membrane vesicles. Nat. Rev. Immunol. 15, 375–387 (2015).
Schwechheimer, C. & Kuehn, M. J. Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat. Rev. Microbiol. 13, 605–619 (2015).
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).
Golovkina, T. V., Shlomchik, M., Hannum, L. & Chervonsky, A. Organogenic role of B lymphocytes in mucosal immunity. Science 286, 1965–1968 (1999).
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).
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).
Sicin´ski, P. et al. Poliovirus type 1 enters the human host through intestinal M cells. Gastroenterology 98, 56–58 (1990).
Wolf, J. L. et al. Intestinal M cells: a pathway for entry of reovirus into the host. Science 212, 471–472 (1981).
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).
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).
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).
This work was supported by the US National Institutes of Health (NIH; grant R01AI116892).
The author declares no competing financial interests.
About this article
Cite this article
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
Gut Pathogens (2021)
Minor alterations in the intestinal microbiota composition upon Rotavirus infection do not affect susceptibility to DSS colitis
Scientific Reports (2021)
Target-based drug discovery, ADMET profiling and bioactivity studies of antibiotics as potential inhibitors of SARS-CoV-2 main protease (Mpro)
Molecular Neurobiology (2021)
Microbial Cell Factories (2020)