Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses

Nat Commun. 2019 Oct 11;10(1):4624. doi: 10.1038/s41467-019-12632-5.

Abstract

Cytosolic mitochondrial DNA (mtDNA) activates cGAS-mediated antiviral immune responses, but the mechanism by which RNA viruses stimulate mtDNA release remains unknown. Here we show that viroporin activity of influenza virus M2 or encephalomyocarditis virus (EMCV) 2B protein triggers translocation of mtDNA into the cytosol in a MAVS-dependent manner. Although influenza virus-induced cytosolic mtDNA stimulates cGAS- and DDX41-dependent innate immune responses, the nonstructural protein 1 (NS1) of influenza virus associates with mtDNA to evade the STING-dependent antiviral immunity. The STING-dependent antiviral signaling is amplified in neighboring cells through gap junctions. In addition, we find that STING-dependent recognition of influenza virus is essential for limiting virus replication in vivo. Our results show a mechanism by which influenza virus stimulates mtDNA release and highlight the importance of DNA sensing pathway in limiting influenza virus replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • DNA, Mitochondrial / immunology*
  • DNA, Mitochondrial / metabolism
  • Encephalomyocarditis virus / immunology
  • HEK293 Cells
  • Host Microbial Interactions
  • Humans
  • Immunity, Innate
  • Influenza A virus / immunology*
  • Signal Transduction
  • Viral Matrix Proteins / immunology*
  • Viral Proteins / immunology*
  • Viral Proteins / metabolism

Substances

  • DNA, Mitochondrial
  • M2 protein, Influenza A virus
  • Viral Matrix Proteins
  • Viral Proteins