Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease

Science. 2016 Apr 22;352(6284):463-6. doi: 10.1126/science.aaf3926.

Abstract

Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Bacterial Infections / etiology
  • Bacterial Infections / immunology*
  • Caspase 1 / metabolism
  • Caspases / metabolism
  • Caspases, Initiator
  • Female
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Influenza A virus / immunology*
  • Influenza, Human / complications
  • Influenza, Human / immunology*
  • Interferon-beta / immunology
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Monocytes / immunology
  • Myxovirus Resistance Proteins / genetics
  • Myxovirus Resistance Proteins / physiology*
  • Neutrophils / immunology
  • Orthomyxoviridae Infections / immunology*
  • Respiratory Tract Infections / immunology*
  • Respiratory Tract Infections / microbiology
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / metabolism
  • Viral Load
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • Membrane Glycoproteins
  • Mx1 protein, mouse
  • Myxovirus Resistance Proteins
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Interferon-beta
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Caspase 1