The Influence of Cytoplasmic Nucleic Acid Sensors on the Adaptive Immune Response

Immune detection of nucleic acids is an essential component of the host response to virus, but how this process influences the adaptive immune response remains incompletely understood. In this study, we analysed the target tissue response to infection with the enterovirus Coxsackie B virus (CVB4). Studies show that the gut mucosa may be an important CVB4 reservoir influencing dissemination to other target organs such as the pancreas. Strains of mice were compared that were either susceptible or resistant to the development of chronic inflammation following viral clearance. Transcriptome analyses of target tissues (GIT and pancreas) showed that increased expression of RNA sensors correlated with the immune response to RNA virus. However, the propensity to develop chronic inflammation long after viral clearance was distinguished by continued high expression of DNA sensors. The cell intrinsic response to CVB4 was also strongly biased toward interferon regulatory factor (IRF)7, rather than IRF3 mediated pathways. Cytoplasmic RIG-like helicases (RIG-I and MDA5) use the signalling adaptor mitochondrial antiviral signalling (MAVS) to activate IRF3 and IRF7, which are both regulators of type I IFN gene expression. The role of MAVS in CVB4 infection was explored in a novel MAVS mutant mouse strain that harbours a point mutation in the transmembrane region that influences mitochondrial localisation of MAVS. In MAVSsnp mice, MAVS was important for both the type 1 interferon response and antibody production in response to CVB4, suggesting that innate genes involved in antiviral sensing influence adaptive immune responses.