Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells

Inflammation observed in SARS-CoV-2-infected patients suggests that inflammasomes, proinflammatory intracellular complexes, regulate various steps of infection. Lung epithelial cells express inflammasome-forming sensors and constitute the primary entry door of SARS-CoV-2. Here, we describe that the NLRP1 in-flammasome detects SARS-CoV-2 infection in human lung epithelial cells. Specifically, human NLRP1 is cleaved at the Q333 site by multiple coronavirus 3CL proteases, which triggers inflammasome assembly and cell death and limits the production of infectious viral particles. Analysis of NLRP1-associated pathways unveils that 3CL proteases also inactivate the pyroptosis executioner Gasdermin D (GSDMD). Subsequently, caspase-3 and GSDME promote alternative cell pyroptosis. Finally, analysis of pyroptosis markers in plasma from COVID-19 patients with characterized severe pneumonia due to autoantibodies against, or inborn errors of, type I interferons (IFNs) highlights GSDME/caspase-3 as potential markers of disease severity. Overall, our findings identify NLRP1 as a sensor of SARS-CoV-2 infection in lung epithelia.

Automated summary

The activation of inflammasomes plays a crucial role in regulating the infection of SARS-CoV-2. Lung epithelial cells serve as the primary entry site of the virus and express the inflammasome-forming sensor NLRP1. The cleavage of NLRP1 by coronavirus 3CL proteases leads to inflammasome assembly, cell death, and reduced production of viral particles. Additionally, these proteases also inactivate the executioner protein Gasdermin D, promoting an alternative form of cell death called pyroptosis. Analysis of pyroptosis markers in COVID-19 patients suggests that GSDME/caspase-3 could potentially serve as markers of disease severity.