TY - JOUR PY - 2022// TI - Inflammasome activation in infected macrophages drives COVID-19 pathology JO - bioRxiv: The Preprint Server for Biology A1 - Sefik, Esen A1 - Qu, Rihao A1 - Junqueira, Caroline A1 - Kaffe, Eleanna A1 - Mirza, Haris A1 - Zhao, Jun A1 - Brewer, J. Richard A1 - Han, Ailin A1 - Steach, Holly R. A1 - Israelow, Benjamin A1 - Blackburn, Holly N. A1 - Velazquez, Sofia A1 - Chen, Y. Grace A1 - Halene, Stephanie A1 - Iwasaki, Akiko A1 - Meffre, Eric A1 - Nussenzweig, Michel A1 - Lieberman, Judy A1 - Wilen, Craig B. A1 - Kluger, Yuval A1 - Flavell, Richard A. SP - 2021.09.27.461948 EP - 2021.09.27.461948 VL - IS - N2 - Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system 1-20. Blocking either viral replication with Remdesivir 21-23 or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.

Language: en

LA - en SN - 2692-8205 UR - http://dx.doi.org/10.1101/2021.09.27.461948 ID - ref1 ER -