Deficient IFN Signaling by Myeloid Cells Leads to MAVS-Dependent Virus-Induced Sepsis

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Although it is well established that the interferon (IFN) signaling pathway restricts infection by many viruses, the key cell types in vivo that contribute to this process remain poorly characterized. To address this question in the context of West Nile virus (WNV) pathogenesis, we infected mice that specifically delete the type I IFN receptor gene (Ifnar) in subsets of myeloid cells, including dendritic cells and macrophages. Remarkably, mice lacking Ifnar expression only in myeloid cell subsets rapidly developed a sepsis-like syndrome that was characterized by enhanced WNV infection and visceral organ injury and caused by massive proinflammatory cytokine production and complement activation. By using additional gene targeted deletion mice, we show that WNV infection triggered signaling through the RIG-I like receptor adaptor protein MAVS to cause complement activation, sepsis, and tissue damage. Indeed, liver damage was minimized in animals lacking specific complement components, or treated with neutralizing anti-complement or anti-TNF-α antibodies. Our results establish how type I IFN signaling in dendritic cells and macrophages restricts infection, controls inflammatory cascades, and prevents pathogenesis in vivo.

Vyšlo v časopise: Deficient IFN Signaling by Myeloid Cells Leads to MAVS-Dependent Virus-Induced Sepsis. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004086
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004086

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