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Shubina M , Tummers B , Boyd DF , Zhang T , Yin C , Gautam A , Guo XJ , Rodriguez DA , Kaiser WJ , Vogel P , Green DR , Thomas PG , Balachandran S
Necroptosis restricts influenza A virus as a stand-alone cell death mechanism
J Exp Med. 2020 Nov 2;217(11)
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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.
1540-9538 Shubina, Maria Tummers, Bart Boyd, David F Zhang, Ting Yin, Chaoran Gautam, Avishekh Guo, Xi-Zhi J Rodriguez, Diego A Kaiser, William J Vogel, Peter Green, Douglas R Thomas, Paul G Balachandran, Siddharth Journal Article United States J Exp Med. 2020 Nov 2;217(11):e20191259. doi: 10.1084/jem.20191259.