The influence of commensal bacteria on infection with enteric viruses

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.

Figure 1. Enteric virus interactions with bacterial surface glycans can facilitate viral stability and binding to target cells

a | The binding of lipopolysaccharide (LPS), or other bacterial polysaccharides, to poliovirus leads to an increase in viral thermostability and resistance to inactivation by dilute chlorine bleach, which has been linked with the delayed release of viral genomes. This increase in viral stability could potentiate viral transmissibility. b | Poliovirus associated with LPS binds to the known poliovirus receptor (PVR) more efficiently on the surface of target cells. Several lines of evidence show that LPS enhancement is conferred by facilitating viral binding to the known PVR: pre-treatment of permissive cells with PVR-specific antibody inhibits viral binding in both the presence and absence of LPS; virus bound to LPS does not gain competency to infect non-PVR-expressing cells; and virus incubated with LPS has increased binding to soluble PVR compared with virus alone. c | Human norovirus infection of B cells is facilitated by commensal bacteria that express the appropriate histo-blood group antigen (HBGA). The first indication that commensal bacteria stimulate human norovirus infection of B cells was provided by the observation that the filtration of virus-positive stool to remove commensal bacteria reduced viral infectivity. Providing direct evidence, the supplementation of filtered stool with HBGA-expressing bacteria fully restores infectivity. E. cloacae, Enterobacter cloacae.

Figure 2. Commensal bacteria can induce a tolerogenic microenvironment that facilitates the establishment of MMTV persistence

Available evidence pertaining to the establishment of mouse mammary tumour virus (MMTV) persistence supports a model whereby MMTV-bound lipopolysaccharide (LPS) activates Toll-like receptor (TLR) signalling on dendritic cells, or macrophages, inducing the secretion of interleukin-6 (IL-6), which acts on B cells to stimulate their secretion of IL-10. In this immunosuppressive microenvironment, MMTV can establish persistence and immunological tolerance is established to MMTV antigens. Several key observations support this model: the establishment of MMTV persistence requires the LPS receptor TLR4 and the immunosuppressive cytokine IL-10; MMTV binds to LPS and this interaction is required for the induction of IL-10; and mice exposed to MMTV-laden milk as pups are tolerant to MMTV antigens later in life. IL-6R, interleukin-6 receptor.

Figure 3. Commensal bacteria can suppress the type III interferon response, facilitating the establishment of murine norovirus persistence

Although the establishment of murine norovirus persistence requires commensal bacteria in immunocompetent mice, the establishment of persistence occurs in a microbiota-independent manner in mice lacking the type III interferon receptor (IFNλR), known as IFNλR-deficient mice. Together with the observations that IFNλ acts on non-haematopoietic cells and that the tropism of murine norovirus is specific to immune cells, a model develops whereby norovirus interactions with commensal bacteria normally suppress the production of antiviral IFNλ (part a). In microorganism-depleted mice, IFNλ is produced and activates the IFNλR in enterocytes or in other bystander cells to indirectly inhibit the establishment of norovirus persistence (part b). In mice lacking functional type III IFN signalling pathways, the establishment of persistence does not require interactions with commensal bacterial because the bystander cells are impaired in their ability to respond to IFNλ (part c).