The Caspase-Activated DNase drives inflammation and contributes to defense against viral infection
Abdul Moeed, Nico Thilmany, Frederic Beck, Bhagya K. Puthussery, Noemi Ortmann, A Haimovici, Mohamed Tarek Badr, Elham Bavafaye Haghighi, Melanie Boerries, Rupert Öllinger, Roland Rad, Susanne Kirschnek, Ian E. Gentle, Sainitin Donakonda, Philipp P. Petric, Jonas F. Hummel, Elisabeth Pfaffendorf, Paola Zanetta, Christoph Schell, Martin Schwemmle, Arnim Weber, Georg Häcker
Abstract
Mitochondria react to infection with sub-lethal signals in the apoptosis pathway. Mitochondrial signals can be inflammatory but mechanisms are only partially understood. We show that activation of the caspase-activated DNase (CAD) mediates mitochondrial pro-inflammatory functions and substantially contributes to host defense against viral infection. In cells lacking CAD, the pro-inflammatory activity of sub-lethal signals was reduced. Experimental activation of CAD caused transient DNA-damage and a pronounced DNA damage response, involving major kinase signaling pathways, NF-κB and cGAS/STING, driving the production of interferon, cytokines/chemokines and attracting neutrophils. The transcriptional response to CAD-activation was reminiscent of the reaction to microbial infection. CAD-deficient cells had a diminished response to viral infection. Influenza virus infected CAD-deficient mice displayed reduced inflammation in lung tissue, higher viral titers and increased weight loss. Thus, CAD links the mitochondrial apoptosis system and cell death caspases to host defense. CAD-driven DNA damage is a physiological element of the inflammatory response to infection.