Necroptosis restricts influenza A virus as a stand-alone cell death mechanism

J Exp Med. 2020 Nov 2;217(11):e20191259. doi: 10.1084/jem.20191259.


Influenza A virus (IAV) activates ZBP1-initiated RIPK3-dependent parallel pathways of necroptosis and apoptosis in infected cells. Although mice deficient in both pathways fail to control IAV and succumb to lethal respiratory infection, RIPK3-mediated apoptosis by itself can limit IAV, without need for necroptosis. However, whether necroptosis, conventionally considered a fail-safe cell death mechanism to apoptosis, can restrict IAV-or indeed any virus-in the absence of apoptosis is not known. Here, we use mice selectively deficient in IAV-activated apoptosis to show that necroptosis drives robust antiviral immune responses and promotes effective virus clearance from infected lungs when apoptosis is absent. We also demonstrate that apoptosis and necroptosis are mutually exclusive fates in IAV-infected cells. Thus, necroptosis is an independent, "stand-alone" cell death mechanism that fully compensates for the absence of apoptosis in antiviral host defense.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Caspase 8 / genetics*
  • Caspase 8 / metabolism
  • Female
  • Gene Knock-In Techniques
  • Host Microbial Interactions / genetics*
  • Host Microbial Interactions / immunology
  • Influenza A virus / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Necroptosis / genetics*
  • Necroptosis / immunology
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / virology
  • RNA-Binding Proteins / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism


  • RNA-Binding Proteins
  • Zbp1 protein, mouse
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Casp8 protein, mouse
  • Caspase 8