Innate immune sensing of influenza A viral RNA through IFI16 promotes pyroptotic cell death
Shalabh Mishra,
Athira S. Raj,
Akhilesh Kumar,
Ashwathi Rajeevan,
Puja Kumari,
Himanshu Kumar
Affiliations
Shalabh Mishra
Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal 462066, MP, India
Athira S. Raj
Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal 462066, MP, India
Akhilesh Kumar
Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal 462066, MP, India
Ashwathi Rajeevan
Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal 462066, MP, India
Puja Kumari
Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal 462066, MP, India
Himanshu Kumar
Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal 462066, MP, India; WPI Immunology, Frontier Research Centre, Osaka University, Osaka 5650871, Japan; Corresponding author
Summary: Programmed cell death pathways are triggered by various stresses or stimuli, including viral infections. The mechanism underlying the regulation of these pathways upon Influenza A virus (IAV) infection is not well characterized. We report that a cytosolic DNA sensor IFI16 is essential for the activation of programmed cell death pathways in IAV infected cells. We have identified that IFI16 functions as an RNA sensor for the influenza A virus by interacting with genomic RNA. The activation of IFI16 triggers the production of type I, III interferons, and also pro-inflammatory cytokines via the STING-TBK1 and Pro-caspase-1 signaling axis, thereby promoting cell death (apoptosis and pyroptosis in IAV infected cells). On the contrary, IFI16 knockdown cells showed reduced inflammatory responses and also prevented cell mortality during IAV infection. Collectively, these results demonstrate the pivotal role of IFI16-mediated IAV sensing and its essential role in activating programmed cell death pathways.
