PT  - JOURNAL ARTICLE
AU  - Brian V. Tsu
AU  - Rimjhim Agarwal
AU  - Nandan S. Gokhale
AU  - Jessie Kulsuptrakul
AU  - Andrew P. Ryan
AU  - Lennice K. Castro
AU  - Christopher M. Beierschmitt
AU  - Elizabeth A. Turcotte
AU  - Elizabeth J. Fay
AU  - Russell E. Vance
AU  - Jennifer L. Hyde
AU  - Ram Savan
AU  - Patrick S. Mitchell
AU  - Matthew D. Daugherty
TI  - Host specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome
AID  - 10.1101/2022.09.21.508960
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.09.21.508960
4099  - http://biorxiv.org/content/early/2022/09/22/2022.09.21.508960.short
4100  - http://biorxiv.org/content/early/2022/09/22/2022.09.21.508960.full
AB  - 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 (3CLpro) 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 3CLpro, including 3CLpro-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 3CLpros, and instead enables sensing of 3C proteases (3Cpro) 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.Competing Interest StatementThe authors have declared no competing interest.