Host specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome

• Published in: bioRxiv 2022-09
• Main Authors: Tsu, Brian V, Agarwal, Rimjhim, Gokhale, Nandan S, Kulsuptrakul, Jessie, Ryan, Andrew P, Castro, Lennice K, Beierschmitt, Christopher M, Turcotte, Elizabeth A, Fay, Elizabeth J, Vance, Russell E, Hyde, Jennifer L, Savan, Ram, Mitchell, Patrick S, Daugherty, Matthew D
• Format: Article
• Language: English
• Subjects: Antagonism; Cell death; Coronaviridae; Coronaviruses; Cytokines; Immunology; Inflammasomes; Inflammation; Proteinase; Severe acute respiratory syndrome coronavirus 2; Single-nucleotide polymorphism
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2022.09.21.508960

Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CL ) encoded by diverse coronaviruses, including SARS-CoV-2, cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CL , including 3CL -mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8’s ability to sense coronavirus 3CL , and instead enables sensing of 3C proteases (3C ) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intra-species variation in inflammasome-mediated viral sensing and immunopathology.