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Rotavirus (RV), a nonenveloped double-stranded RNA (dsRNA) virus, causes life-threatening diarrhea in hundreds of thousands of children annually. RV enters its host orally and primarily infects ileal villous epithelial cells, which exist amidst a large diverse ecosystem of microorganisms collectively called the gut microbiota. Ablation of the microbiota in mice via germ-free (GF) or antibiotic approaches impedes infection with mouse mammary tumor virus, poliovirus, reovirus, and RV. Administration of bacterial products, including LPS, CpG DNA, and flagellin, can protect against viral infection. For example, we discovered that flagellin inducesTLR5-mediated innate lymphoid cell (ILC) interleukin-22 (IL-22) production and NLRC4-mediated IL-18 release, which prevent sand cures RV infection. In addition to this, our study shows that segmented filamentous bacteria (SFB) are sufficient to protect mice from RV infection and associated diarrhea. This protection is independent of previously defined RV inhibitors and is independent of immune cells.
RV primarily infects villus epithelial cells, causing severe diarrhea in young hosts and moderate distress in adults. Although RV is typically cleared within 10 days, immunodeficient humans and mice, develop chronic RV infection. We refer to such RV-susceptible Rag1-KO mice as "JAX-RAG" and the aforementioned RV-resistant Rag1-KO mice as "GSU-RAG." Studies have shown that transmissible factors present in GSU-lager feces protect against rotavirus infection and its main associated diseases.
Research shows that microbes in GSU-RAG feces that might otherwise protect against RV infection are normally constrained by a mechanism involving humoral and cell-mediated immunity. We next considered the possibility that JAX-RAG and GSU-RAG mice might display differences in intestinal leukocytes that mediated resistance to RV. Results show that microorganism(s)present in the GSU-RAG microbiota reduced RRV infectivity. Such a reduction correlated with reduced levels of RV attachment to epithelial cells, as determined by qRT-PCR of epithelial cells inoculated with RV. Besides, the capacity ofGSU-RAG feces to suppress viral infection in vitro was not specific for RV but alsoextended to VSV and influenza A virus (IAV). These results suggest that microbes in GSU-RAG feces may have broad antiviral activity.
We next sought to define the protective component of GSU-RAG microbiota, we identified candidate bacteria mediating RV resistance through microbiome analysis. These results indicate that Candidatus arthromitus (SFB) are present in RV-resistant immunodeficient mice and can be transferred via FT that confers RV resistance, suggesting that SFB might contribute to RV resistance. Genome sequencing found that the genomes of both strains were assembled with more than 94% coverage, referred to here as "Pasteur-SFB" (SFB-P), the "GSUSFB" (SFB-G) strain. SFB-G contained 133 genes not present (at a similarity of more than 90%) in SFB-P, and the genes unique to SFB-G were of broad function.
Having characterized the effect of SFB-G on RV infectivity and gut epithelium, we next investigated the extent to which it was sufficient to promote RV resistance. The result shows that levels of SFB in the intestine are correlated with the extent of the RV-resistant phenotype and that other microbes present in GSU-RAG mice promote SFB colonization. Last, we determined whether SFB-G colonization of the ileum was sufficient to ameliorate RV-induced disease in immunocompetent hosts. We found that SFB-G largely recapitulated the capacity of GSU-RAG feces to suppress RV-induced diarrhea in newborn WT mice, highlighting the potential utility of select gut microbiota members to prevent and treat viral infections.
Enteric viral infections remain a major public health challenge. Although most humans are exposed to RV multiple times, there is substantial heterogeneity in disease penetrance and severity both geographically and within a given population. The environmental determinants of RV disease heterogeneity are not well defined. Because enteric viruses first encounter host cells amidst microbiota, we hypothesized that microbiota composition might influence susceptibility to RV infection. Studies seeking to broadly define the role of the microbiota in enteric viral infections revealed that mice lacking a microbiota are protected against RV and other enteric viruses, suggesting that such viral pathogens have developed a means to exploit the gut microbiota to aid their infection. We found that the extent to which the microbiota aids or impedes viral infection is dependent on the specific microbiota composition of the host, with one bacterial species in particular, SFB, being a strong contributor to resistance to RV infection and disease.
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