Abstract
ABSTRACTChronic viral infections represent a major challenge to the host 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-27 receptor (IL-27R) signaling promoted control of LCMV Cl13 as early as days 1 and 5 after infection and that il27p28 transcripts 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 increased il27p28 in a Toll-like receptor 7 (TLR7)-dependent fashion. Notably, mice deficient in an IL-27-specific receptor, WSX-1, exhibited a pleiotropy of innate and adaptive immune alterations after chronic lymphocytic choriomeningitis virus (LCMV) infection, including compromised NK cell cytotoxicity and antibody responses. While, the majority of these immune alterations appeared to be cell extrinsic, cell-intrinsic IL-27R was necessary to maintain early pDC numbers, which, alongside lower IFN-I transcription in CD11b+ DCs 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 antiviral 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.IMPORTANCE Persistently replicating pathogens, such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, represent major health problems worldwide. These infections impose a long-term challenge on the host immune system, which must be heavily and continuously regulated to keep pathogen replication in check without causing fatal immunopathology. Using a persistently replicating rodent pathogen, LCMV, in its natural host, we identified the cellular sources and effects of one important regulatory pathway, interleukin-27 receptor WSX-1 signaling, 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 signaling 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.
Highlights
IMPORTANCE Persistently replicating pathogens, such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, represent major health problems worldwide
We have previously reported that WSX-1 is required for long-term control of Lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl13), and seems to regulate the viral burden earlier in infection [43]
We found that Il27raϪ/Ϫ mice had significantly increased viremia at days 5, 9, and 11 p.i. with LCMV Cl13 compared to WT mice, with similar viral loads seen at day 15 (Fig. 1A)
Summary
IMPORTANCE Persistently replicating pathogens, such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, represent major health problems worldwide These infections impose a long-term challenge on the host immune system, which must be heavily and continuously regulated to keep pathogen replication in check without causing fatal immunopathology. Infection by these pathogens often results in heavily regulated immune responses that aim to keep the persistent virus in check without causing fatal immunopathology Such immune regulation during chronic viral infections includes hypofunctionality of CD4ϩ and CD8ϩ T cells and delayed antibody production, as well as rapidly attenuated, but sustained, type I IFN (IFN-I) responses (reviewed in reference 1). IL-27 influences other immune cells, regulating natural killer (NK) cell cytotoxicity and cytokine secretion [38]; upregulating CD39 on conventional dendritic cells (DCs), which results in enhanced suppression of T cell responses [39]; and inhibiting viral replication in HIV- and HCV-infected cells in vitro [40,41,42]
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