Gut homeostasis is regulated by complex interactions between genetic and environmental factors and the host’s immune system. When this homeostasis is disrupted, gut inflammation ensues. Microbial imbalance, also known as dysbiosis, plays a critical role in intestinal pathology; however, previous studies have only focused on commensal bacteria despite metagenomic studies showing that a variety of resident viruses also inhabit the healthy gut.

 

The most abundant viral group in the healthy gut includes temperate bacteriophages, which can integrate their genomes into their host bacterium’s chromosome (1, 2). Several different types of eukaryotic viruses, such as poxviruses, herpesviruses, picornaviruses and plant-infecting viruses, are also present in the healthy gut virome, but they are fewer in number and are mostly derived from diet (3, 4). While many pathogenic viruses – norovirus being a main culprit­ – have been linked to gut inflammation, not much is known about the immunological role of resident viruses in the healthy gut.

 

Pattern-recognition receptors (PRRs) initiate a crosstalk between resident viruses and the innate immune system by identifying viral components, such as single- and double-stranded RNA (ssRNA and dsRNA, respectively) and viral proteins. PRRs particularly important for detecting dsRNA and ssRNA are Toll-like receptors (TLRs), TLR3 and TLR7, respectively. TLRs recognize invading microbes and activate signaling pathways that launch immune and inflammatory responses to destroy the invaders. A previous study showed that commensal bacteria-depleted mice recovered from severe gut inflammation following administration of lipoteichoic acid, a TLR2 agonist or lipopolysaccharide (LPS), a TLR4 agonist (5). This result suggests that the protective effect of TLRs on gut inflammation extends beyond recognition of commensal bacteria to other microbes such as viruses.

 

What role do resident viruses play in regulating intestinal homeostasis, and how do these viruses interact with the host innate immune system? A recent study by Yang et al. in Immunity sheds light on these questions (6). The researchers found that treating mice with an antiviral cocktail before dextran sulfate sodium (DSS) treatment resulted in more severe colitis compared to untreated mice. Antiviral treatment led to reduced viral particles and community-wide changes in resident gut viral DNA and RNA metagenomes. Treatment of wild-type mice with TLR3 or TLR7 agonists and inactivated rotavirus improved symptoms, and Tlr3-/- and Tlr7-/- mice were more susceptible to DSS-induced colitis. Treatment with TLR3+7 agonists resulted in an increase of IFN-β production by plasmacytoid dendritic cells that were isolated from inflamed mouse colon. The researchers also investigated the role of enteric virus signaling at onset and on the severity of inflammatory bowel disease (IBD) in humans by analyzing the associations of TLR3 and TLR7 variants and susceptibility to IBD using direct sequencing and genotyping of the two gene variants. Their results suggest that the TLR3+7-mediated host defense mechanism plays an indispensable role in gut inflammation regulation. In summary, these findings demonstrate that resident gut viruses reduce inflammation via TLR3+7-mediated IFN-β production. Until now, intestinal viruses were regarded as harmful or neutral to the host but this study shows that in some cases, intestinal viruses might be beneficial.

 

Interested in learning more about microbial detection and host-response analysis? Download the recording and slides from our recent “Microbial Pathogenesis and Host-immune Response” webinar.

 

References

  • 1. Minot, S. et al. (2013) Rapid evolution of the human gut virome. Proc Natl Acad Sci U S A. 110, 30. Link
  • 2. Reyes, A. et al. (2010) Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature. 466, 7304. Link
  • 3. Kim, M-S. et al. (2011) Diversity and abundance of single-stranded DNA viruses in human feces. Appl Environ Microbiol. 77, 22. Link
  • 4. Zhang, T. et al. (2006) RNA viral community in human feces: prevalence of plant pathogenic viruses. PLoS Biol. 4, 1. Link
  • 5. Rakoff-Nahoum, S. et al. (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 118, 2. Link
  • 6. Yang, J.Y. et al. (2016) Enteric viruses ameliorate gut inflammation via Toll-like receptor 3 and Toll-like receptor 7-mediated interferon-β production. Immunity 44, 4. Link

 

Author: