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.