Viral proteases activate the CARD8 inflammasome in the human cardiovascular system

Autor: Rhea Nadkarni, Wern Cui Chu, Cheryl Q.E. Lee, Yasir Mohamud, Lynn Yap, Gee Ann Toh, Sheryl Beh, Radiance Lim, Yiyun Michelle Fan, Yizhuo Lyanne Zhang, Kim Robinson, Karl Tryggvason, Honglin Luo, Franklin Zhong, Lena Ho
Přispěvatelé: Lee Kong Chian School of Medicine (LKCMedicine), Skin Research Institute of Singapore, A*STAR
Rok vydání: 2022
Předmět:
Zdroj: Journal of Experimental Medicine. 219
ISSN: 1540-9538
0022-1007
DOI: 10.1084/jem.20212117
Popis: Nucleotide-binding oligomerization domain (NBD), leucine-rich repeat (LRR) containing protein family (NLRs) are intracellular pattern recognition receptors that mediate innate immunity against infections. The endothelium is the first line of defense against blood-borne pathogens, but it is unclear which NLRs control endothelial cell (EC) intrinsic immunity. Here, we demonstrate that human ECs simultaneously activate NLRP1 and CARD8 inflammasomes in response to DPP8/9 inhibitor Val-boro-Pro (VbP). Enterovirus Coxsackie virus B3 (CVB3)-the most common cause of viral myocarditis-predominantly activates CARD8 in ECs in a manner that requires viral 2A and 3C protease cleavage at CARD8 p.G38 and proteasome function. Genetic deletion of CARD8 in ECs and human embryonic stem cell-derived cardiomyocytes (HCMs) attenuates CVB3-induced pyroptosis, inflammation, and viral propagation. Furthermore, using a stratified endothelial-cardiomyocyte co-culture system, we demonstrate that deleting CARD8 in ECs reduces CVB3 infection of the underlying cardiomyocytes. Our study uncovers the unique role of CARD8 inflammasome in endothelium-intrinsic anti-viral immunity. Nanyang Technological University National Research Foundation (NRF) Published version This work is supported by NRF-NRFF2017-05 from the National Research Foundation and MOH-000439 from the National Medical Research Council/Ministry of Health awarded to L. Ho, and NRF-NRFF11-2019-0006 from the National Research Foundation and Nanyang Assistant Professorship (Nanyang Technological University) awarded to F. Zhong.
Databáze: OpenAIRE
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