# Induction of DNA-mediated immune responses by bacterial extracellular vesicles results in control of murine norovirus infection

## TL;DR

Bacterial extracellular vesicles trigger DNA-sensing immune pathways that help control norovirus infection in mice.

## Contribution

This study reveals that bacterial EVs activate DNA-mediated type I IFN pathways to suppress norovirus replication.

## Key findings

- Bacterial EVs induce cytosolic DNA pathways and type I IFN production.
- Loss of STING or TLR9 reduces IFNβ and allows MNV replication.
- Gram-negative bacterial EVs offer a new mechanism for microbiota-mediated antiviral defense.

## Abstract

Commensal bacteria have been a centerpiece for understanding interkingdom impacts on viral replication. Multiple groups have investigated the roles commensal bacteria played in regulating enteric virus infection and it has been found that the mechanisms through which this regulation occurs varies between the viruses and bacteria explored. For noroviruses, commensal bacteria enhance or suppress viral infection in a region-dependent manner. Recently, it was found that the extracellular vesicles (EVs) produced by commensal bacteria can suppress norovirus infection. In this study, we used murine norovirus (MNV) to probe the immunological mechanisms induced by bacterial EVs. Global analysis of gene expression pointed to induction of cytosolic DNA pathways; thus, we evaluate the DNA content packaged within the bacterial EVs and DNA-sensing pathways that activate type I interferons (IFN), including STING and TLR9. Our results showed that loss of sting or tlr9, significantly decreased IFNβ production and recovered MNV replication in the presence of bEVs. Collectively, these data demonstrated bEVs of certain gram-negative bacteria can initiate antiviral DNA-mediated type I IFN production pathways and that these pathways are involved in the suppression of MNV replication. These findings expose novel mechanisms through which the native microbiota aids the host in controlling an enteric viral infection and offers a fresh perspective on interkingdom host‒microbiota interactions.