Journal of virology 2018 03 28() pii 10.1128/JVI.02196-17
Chronic viral infections represent a major challenge to host’s immune response and a unique network of immunological elements, including cytokines, are required for their containment. By using a model persistent infection with the natural murine pathogen lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) we investigated the role of one such cytokine, interleukin 27 (IL-27), in the control of chronic infection. We found that IL-27R signalling promoted control of LCMV Cl13 as early as day 1 and 5 after infection and thattranscripts were rapidly elevated in multiple subsets of dendritic cells (DCs) and myeloid cells. In particular, plasmacytoid DCs (pDCs), the most potent type-1-interferon (IFN-I) producing cells, significantly increasedin a TLR7 dependent fashion. Notably, mice deficient in IL-27 specific receptor (R), WSX-1, exhibited a pleiotropy of innate and adaptive immune alterations after chronic LCMV infection, including compromised NK cell cytotoxicity and antibody responses. While, the majority of these immune alterations appeared cell-extrinsic, cell-intrinsic IL-27R was necessary to maintain early pDC numbers, which, alongside lower IFN-I transcription in CD11bDCs and myeloid cells, may explain the compromised IFN-I elevation that we observed early after LCMV Cl13 infection in IL-27R-deficient mice. Together these data highlight the critical role of IL-27 in enabling optimal anti-viral immunity early and late after infection with a systemic persistent virus and suggest that a previously unrecognized positive feedback-loop mediated by IL-27 in pDCs might be involved in this process.Persistently replicating pathogens such as Human Immunodeficiency virus, Hepatitis B virus and Hepatitis C virus represent a major health problem worldwide. These infections impose a long-term challenge on the host immune system, which must be heavily and continuously regulated to keep the pathogen replication in check without causing fatal immunopathology. Using a persistently replicating rodent pathogen, lymphocytic choriomeningitis virus (LCMV), in its natural host we identified the cellular sources and effects of one important regulatory pathway, the interleukin-27 receptor WSX-1 signalling, that is required for both very early and late restriction of chronic (but not acute) infection. We found that WSX-1 was necessary to promote innate immunity and the development of aberrant adaptive immune responses. This not only highlights the role of IL-27 receptor signalling in regulating distinct host responses that are known to be necessary to control chronic infections but also positions IL-27 as a potential therapeutic target for their modulation.