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IL-27R signalling mediates early viral containment and impacts innate and adaptive immunity after chronic lymphocytic choriomeningitis virus infection.

IL-27R signalling mediates early viral containment and impacts innate and adaptive immunity after chronic lymphocytic choriomeningitis virus infection.
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Harker JA, Wong KA, Dallari S, Bao P, Dolgoter A, Jo Y, Wehrens EJ, Macal M, Zuniga EI,


Harker JA, Wong KA, Dallari S, Bao P, Dolgoter A, Jo Y, Wehrens EJ, Macal M, Zuniga EI, (click to view)

Harker JA, Wong KA, Dallari S, Bao P, Dolgoter A, Jo Y, Wehrens EJ, Macal M, Zuniga EI,

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Journal of virology 2018 03 28() pii 10.1128/JVI.02196-17

Abstract

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.

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