Editors' ChoiceHost-Pathogen Interactions

The A-to-Z of influenza infection

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Science Signaling  31 Mar 2020:
Vol. 13, Issue 625, eabb9158
DOI: 10.1126/scisignal.abb9158

Z-RNA produced by influenza virus stimulates necroptosis and activates neutrophils in infected tissue.

Infection with influenza A virus (IAV) triggers necroptosis in a manner dependent on RIPK3 and its downstream effector MLKL and the RNA-binding protein ZBP1. Zhang et al. investigated the molecular mechanisms that link ZBP1 to the necroptosis pathway. Defective viral genomes (DVGs) are incomplete products of viral replication. ZBP1 bound to DVGs in the nuclei of infected cells. Phosphorylated and activated MLKL appeared in the nuclei of IAV-infected cells, and infection by viral strains that generated greater amounts of DVGs induced MLKL phosphorylation earlier than did infection by those strains that generated lesser amounts of DVGs. The RNA in DVGs generated by IAV and other orthomyxoviruses was in the Z-conformation, rather than the standard A-conformation. A ZBP1 mutant that lacked the ability to bind to Z-RNAs did not translocate to the nucleus or associate with RIPK3 and MLKL. Conversely, cells expressing a ZBP1 mutant that constitutively localized to the nucleus died faster and to a greater extent when infected with IAV than did cells expressing wild-type ZBP1. IAV infection induced the breakdown of nuclear envelopes in a manner that was dependent on MLKL and therefore necroptosis (and not apoptosis) and that was mimicked by expression of a nuclear-localized MLKL, albeit in a slower fashion. Supernatant from MEFs expressing nuclear-localized MLKL activated neutrophils (as assessed by NET formation) to a greater extent than did supernatant from MEFs expressing cytosol-localized MLKL. More Mlkl–/– and wild-type mice survived IAV infection than did Ripk3–/– or Zbp1–/– mice, suggesting that IAV-induced cell death was mediated through necroptosis and not apoptosis. Neutrophil infiltration was decreased in the lungs of Mlkl–/– mice compared with those of Mlkl+/+ mice, and supernatant from IAV-infected Mlkl–/– MEFs induced NET formation in neutrophils to a lesser extent than that from Mlkl+/+ MEFs. These results suggest that ZBP1 activated by Z-RNAs produced by orthomyxoviruses such as IAV promotes necroptotic cell death mediated by RIPK3 and MLKL that results in neutrophil activation and subsequent inflammatory responses.

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