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

Date Published: April 17, 2014

Publisher: Public Library of Science

Author(s): Amelia K. Pinto, Hilario J. Ramos, Xiaobo Wu, Shilpa Aggarwal, Bimmi Shrestha, Matthew Gorman, Kristin Y. Kim, Mehul S. Suthar, John P. Atkinson, Michael Gale Jr, Michael S. Diamond, Michaela U. Gack.

http://doi.org/10.1371/journal.ppat.1004086

Abstract

The type I interferon (IFN) signaling response limits infection of many RNA and DNA viruses. To define key cell types that require type I IFN signaling to orchestrate immunity against West Nile virus (WNV), we infected mice with conditional deletions of the type I IFN receptor (IFNAR) gene. Deletion of the Ifnar gene in subsets of myeloid cells resulted in uncontrolled WNV replication, vasoactive cytokine production, sepsis, organ damage, and death that were remarkably similar to infection of Ifnar−/− mice completely lacking type I IFN signaling. In Mavs−/−×Ifnar−/− myeloid cells and mice lacking both Ifnar and the RIG-I-like receptor adaptor gene Mavs, cytokine production was muted despite high levels of WNV infection. Thus, in myeloid cells, viral infection triggers signaling through MAVS to induce proinflammatory cytokines that can result in sepsis and organ damage. Viral pathogenesis was caused in part by massive complement activation, as liver damage was minimized in animals lacking complement components C3 or factor B or treated with neutralizing anti-C5 antibodies. Disease in Ifnar−/− and CD11c Cre+Ifnarf/f mice also was facilitated by the proinflammatory cytokine TNF-α, as blocking antibodies diminished complement activation and prolonged survival without altering viral burden. Collectively, our findings establish the dominant role of type I IFN signaling in myeloid cells in restricting virus infection and controlling pathological inflammation and tissue injury.

Partial Text

Type I interferons (IFN) are a family of antiviral cytokines that are produced early in response to viral infection [1]. RNA intermediates of viral replication are recognized by cytosolic and endosomal pattern recognition receptors (PRR), such as RIG-I-like receptors (RLR) or Toll-like receptors (TLR), which signal through adaptor molecules (e.g., MAVS, TRIF, and MyD88) and transcription factors (e.g., IRF-3 and IRF-7) to induce type I IFN expression and secretion. Type I IFNs bind to a heterodimeric receptor (IFNAR) and mediate pleiotropic effects downstream of a canonical Janus kinase (JAK)-Signal transducers and activators of transcription (STAT) signaling pathway. This results in the induction of antiviral IFN-stimulated genes (ISGs), activation of antigen-presenting cells, and regulation of cytokine and chemokine production (reviewed in [2]). Although IFNAR is expressed on all nucleated cells, individual cell types may respond differently to signaling by type I IFN, as evidenced by overlapping yet distinct transcriptional programs [3], [4].

Although the contribution of type I IFN signaling to the control of viral infection in vivo is established, its importance in specific cell subsets remains less well understood. We evaluated the function of type I IFN signaling in myeloid cells in vivo against WNV infection. We targeted these cells because prior studies had indicated that WNV replicated preferentially in CD11b+ and CD11c+ cells [12], [45]. A striking phenotype was observed after WNV infection of CD11c or LysM Cre+Ifnarf/f mice, as these animals succumbed with a similar rate and kinetics compared to the complete gene deletion Ifnar−/− mice. In contrast, deletion of IFNAR expression only on B cells (CD19 Cre+Ifnarf/f) showed a phenotype after WNV infection that resembled the Cre−Ifnarf/f mice. Viral burden in several organs of CD11c Cre+Ifnarf/f mice was markedly elevated and approached that seen in Ifnar−/− mice. Our experiments revealed a dominant antiviral effect in vivo of type I IFN signaling in myeloid cells, either CD11c+ cells or MØ/monocytes/granulocytes. Pathological analyses showed preferential WNV infection of Ifnar−/− myeloid cells, and this resulted in “cytokine storm”, which was associated with liver and kidney damage, and rapid death. High levels of WNV RNA in Ifnar−/− myeloid cells triggered uncontrolled production of proinflammatory cytokines, pathological complement induction and activation, which together caused a sepsis-like syndrome. This phenotype did not occur universally: whereas 100% of Ifnar−/− mice succumbed to infection with the arthritogenic CHIKV alphavirus, no disease or lethality was observed in CD11c or LysM Cre+Ifnarf/f mice.

 

Source:

http://doi.org/10.1371/journal.ppat.1004086

 

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