The dark side of the gut: Virome-host interactions in intestinal homeostasis and disease

Abstract

The diverse enteric viral communities that infect microbes and the animal host collectively constitute the gut virome. Although recent advances in sequencing and analysis of metaviromes have revealed the complexity of the virome and facilitated discovery of new viruses, our understanding of the enteric virome is still incomplete. Recent studies have uncovered how virome-host interactions can contribute to beneficial or detrimental outcomes for the host. Understanding the complex interactions between enteric viruses and the intestinal immune system is a prerequisite for elucidating their role in intestinal diseases. In this review, we provide an overview of the enteric virome composition and summarize recent findings about how enteric viruses are sensed by and, in turn, modulate host immune responses during homeostasis and disease.

Figure 1.

Indirect and direct influences of bacteriophages on immune responses. (1) Phage-mediated bacterial cell lysis can release PAMPs, which can transit through the intestinal epithelium and induce proinflammatory responses. Bacteriophage tail adhesins can bind LPS to dampen LPS-induced immune responses. (2) In the case of imbalanced phage communities, bacteriophage infection may dramatically influence the host bacterial community and lead to overgrowth of pathogens. The needle domain of the bacteriophage tail fiber region can bind and sequester iron ions and prevent pathogen overgrowth in the intestine. (3) Transfer of prophage-encoded genes can influence the pathogenicity of bacterial hosts and provide immune evasion capacity by directly inhibiting phagocytic cells. (4–6) Phages may also directly pass through damaged epithelial cells (4) or cross through the intestinal epithelium by nonspecific transcytosis (5) or via specific recognition of eukaryotic cells via structures that resemble bacterial receptors (6). These invading phages can interact with the intestinal immune system to induce pro- or anti-inflammatory responses and production of phage-specific neutralizing antibodies. Image created with BioRender.

Figure 2.

Eukaryotic virus interactions with the intestinal immune system. In homeostatic states, commensal viruses stimulate basal type I IFN and IL-15 expression that maintains the antiviral state and sustains intestinal homeostasis. Type I IFNs stimulate IL-22 production from innate lymphoid cells to protect IECs, and IL-15 promotes IEL biogenesis. In the case of enteric viral infections, IFN-λ is induced, likely from epithelial cells, to protect IECs from epithelial tropic viruses including rotavirus, NoV, and astrovirus. Viral pathogens can also transit through the epithelium to infect or induce immune responses from lymphocytes or phagocytes in the lamina propria. The induction of type I IFNs mediates broad systemic control of infections but can also contribute to consequent immune pathology. During viral infection, intestinal phagocytes including lamina propria DCs, macrophages, and DCs in the epithelial dome of Peyer’s patches can also sample viral antigens at various sites. Antigen-laden DCs migrate to the mesenteric lymph nodes, where they present processed antigen and induce T and B cell responses. Induced B cells can differentiate into PCs, which home to the lamina propria and secrete antigen-specific IgG, IgM, and IgA. These Igs transcytose across the epithelial cell layer to provide protection against intestinal viral infection. Solid lines indicate the migration of immune cells, while dashed lines indicate secretion of antibodies and cytokines to the intestinal lumen. Image created with BioRender.