Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity

Sci Rep. 2015 Dec 2;5:17577. doi: 10.1038/srep17577.

Abstract

Influenza virus (IFV) infection is a common cause of severe viral pneumonia associated with acute respiratory distress syndrome (ARDS), which is difficult to control with general immunosuppressive therapy including corticosteroids due to the unfavorable effect on viral replication. Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins, and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in Card9-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production, and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV in vitro, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • CARD Signaling Adaptor Proteins / deficiency*
  • CARD Signaling Adaptor Proteins / immunology
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Immunity, Innate*
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / pathology
  • Pneumonia, Viral / genetics
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / pathology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Syk Kinase
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology

Substances

  • CARD Signaling Adaptor Proteins
  • Card9 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse