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IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus.

ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was also enhanced when IL-21 signaling was blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFN? induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type I IFN in the innate immune response to MRSA.

SUBMITTER: Spolski R

PROVIDER: S-EPMC6504231 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to <i>Staphylococcus aureus</i>.

Spolski Rosanne R West Erin E EE Li Peng P Veenbergen Sharon S Yung Sunny S Kazemian Majid M Oh Jangsuk J Yu Zu-Xi ZX Freeman Alexandra F AF Holland Stephen M SM Murphy Philip M PM Leonard Warren J WJ

eLife 20190416

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human per ...[more]

PMID: 30969166

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Project description:IntroductionThe refractory and recurrent nature of chronic staphylococcal osteomyelitis may be due, at least in part, to the ability of Staphylococcus aureus to invade and persist within bone-forming osteoblasts. However, osteoblasts are now recognized to respond to S. aureus infection and produce numerous immune mediators and bone regulatory factors that can shape the host response. Type I interferons (IFNs) are best known for their antiviral effects, but it is becoming apparent that they impact host susceptibility to a wide range of pathogens including S. aureus.MethodsHere, we have assessed the local expression of IFN-β by specific capture ELISA in an established in vivo mouse model of staphylococcal osteomyelitis. RNA Tag-Seq analysis, specific capture ELISAs, and/or immunoblot analyses, were then used to assess the expression of type I IFNs and select IFN stimulated genes (ISGs) in S. aureus infected primary murine osteoblasts. The effect of IFN-β on intracellular S. aureus burden was assessed in vitro following recombinant cytokine treatment by serial colony counts of liberated bacteria.ResultsWe report the presence of markedly elevated IFN-β levels in infected bone tissue in a mouse model of staphylococcal osteomyelitis. RNA Tag-Seq analysis of S. aureus infected osteoblasts showed enrichment of genes associated with type I IFN signaling and ISGs, and elevated expression of mRNA encoding IFN-β and ISG products. IFN-β production was confirmed with the demonstration that S. aureus induces its rapid and robust release by osteoblasts in a dose-dependent manner. Furthermore, we showed increased protein expression of the ISG products IFIT1 and IFIT3 by infected osteoblasts and demonstrate that this occurs secondary to the release of IFN-β by these cells. Finally, we have determined that exposure of S. aureus-infected osteoblasts to IFN-β markedly reduces the number of viable bacteria harbored by these cells.DiscussionTogether, these findings indicate an ability of osteoblasts to respond to bacteria by producing IFN-β that can act in an autocrine and/or paracrine manner to elicit ISG expression and mitigate S. aureus infection.

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IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus.

Publications

IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to <i>Staphylococcus aureus</i>.

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