IFN-I and IL-22 mediate protective effects of intestinal viral infection

Abstract

Products derived from bacterial members of the gut microbiota evoke immune signaling pathways from the host that promote immunity and barrier function in the intestine. How immune reactions to enteric viruses support intestinal homeostasis is unknown. Recently, we demonstrated that infection by murine norovirus (MNV) reverses intestinal abnormalities upon depletion of bacteria, indicating that an intestinal animal virus can provide cues to the host that are typically attributed to the microbiota. Here, we elucidate mechanisms by which MNV evokes protective responses from the host. We identify an important role for the viral protein NS1/2 in establishing local replication and a type I interferon (IFN-I) response in the colon. We further show that IFN-I acts on intestinal epithelial cells to increase the proportion of CCR2-dependent macrophages and IL-22 producing innate lymphoid cells (ILCs), which in turn promote pSTAT3 signaling in intestinal epithelial cells and protection from intestinal injury. Additionally, we demonstrate that MNV provides a striking IL-22 dependent protection against early life lethal infection by Citrobacter rodentium. These findings demonstrate novel ways in which a viral member of the microbiota fortifies the intestinal barrier during chemical injury and infectious challenges.

STAT1-dependent tolerance of intestinal viral infection

“…Experimental infection of volunteers has demonstrated that human norovirus (huNoV) can establish persistent infection for weeks or months after resolution of clinical symptoms, and despite high viral loads some patients never experience clinical symptoms 48 . These results, together with the demonstration that MNV can confer host-protective effects in mice 7, 10 , suggest that norovirus infection fits the profile of mutualism; however, the host mechanisms facilitating tolerance of this infection are not well understood 10, 49 . Here, we describe profound immune dysregulation following MNV CR6 infection of STAT1-deficient mice.…”

“…MNV CR6 (CR6) demonstrates features of a mutualistic host-microbe interaction and is an attractive model to interrogate commensal tolerance to a eukaryotic virus. In addition to providing supportive signals in immunosufficient GF mice 7, 10 , this strain can establish persistent colonic infection with continued shedding for at least two months in the absence of any detectable clinical or histopathological signs in wildtype (WT) mice 11 . Once MNV was identified 12 , sentinel screening of animal units across North America and Europe identified its presence in >30% of facilities 13 , raising concerns that its presence or absence could contribute to microbiota-induced differences in disease models.…”

Altered immunity of laboratory mice in the natural environment is associated with fungal colonization

“…However, these changes were modest 110 compared with the large increase in Bacteroides reported in a prior study examining the 111 microbiota of wild mice (6), likely reflecting the fact that in our system, adult mice are released 112 into the wild environment with an intact microbiota. Intestinal colonization by commensal fungi 113 (mycobiota) can also contribute to immunity (8)(9)(10)(11)(12)(13)(14)(15)(16). Quantification of fungal burden by qPCR of 114 the conserved ITS region on the same samples above indicated that rewilded mice harbor a 115 significant increase in intestinal colonization by fungi compared with lab mice (Fig.…”

“…Bacterial 16S rRNA gene was amplified at the V4 region using primer pairs and paired-end amplicon sequencing was performed on the Illumina MiSeq system as previously described (8). Sequencing reads were processed using the DADA2 pipeline in the QIIME2 software package.…”

“…ITS2 sub-region extracted sequences were then denoised with deblur and a trim-length of 150 against the UNITE fungal database reference sequences (version 7) (13,14). Finally, the UNITE database was used to train a naïve 8 Bayes classifier and to assign fungal taxonomies in QIIME2 (15). The community matrix was subsampled at a depth of 906 sequences per sample and Bray-Curtis distances and alpha diversity metrics (observed otus) were calculated within QIIME2.…”