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Proc Natl Acad Sci U S A
. 2022 May 24;119(21):e2202012119.
doi: 10.1073/pnas.2202012119. Epub 2022 May 19.
Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis
Mostafa M Eltobgy 1 2 3 , Ashley Zani 1 3 , Adam D Kenney 1 3 , Shady Estfanous 1 3 4 , Eunsoo Kim 3 5 , Asmaa Badr 1 3 , Cierra Carafice 1 3 , Kylene Daily 1 3 , Owen Whitham 1 3 , Maciej Pietrzak 6 , Amy Webb 6 , Jeffrey Kawahara 1 3 , Adrian C Eddy 1 3 , Parker Denz 1 3 , Mijia Lu 3 5 , Mahesh Kc 3 7 , Mark E Peeples 3 7 , Jianrong Li 3 5 , Jian Zhu 3 8 , Jianwen Que 9 , Richard Robinson 1 3 , Oscar Rosas Mejia 1 3 , Rachael E Rayner 3 5 , Luanne Hall-Stoodley 1 3 , Stephanie Seveau 1 3 , Mikhail A Gavrilin 3 , Xiaoli Zhang 6 , Jeronay Thomas 10 , Jacob E Kohlmeier 10 , Mehul S Suthar 10 11 12 , Eugene Oltz 1 , Andrea Tedeschi 13 , Frank H Robledo-Avila 14 , Santiago Partida-Sanchez 14 , Emily A Hemann 1 3 , Eman Abdelrazik 15 , Adriana Forero 1 3 , Shahid M Nimjee 16 , Prosper N Boyaka 3 5 , Estelle Cormet-Boyaka 3 5 , Jacob S Yount 1 3 , Amal O Amer 1 3
Affiliations
- PMID: 35588457
- DOI: 10.1073/pnas.2202012119
Abstract
SignificanceWe report the discovery of fundamental roles for the noncanonical inflammasome molecule Caspase-4/11 in promoting pathological inflammatory and prothrombotic pathways in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Our work demonstrates that Caspase-11 has a broader role in immune responses beyond its previously appreciated effects in bacterial infections. Further, we show that Caspase-11-deficient mice infected with SARS-CoV-2 fare significantly better in terms of overall illness, lung inflammation, and thrombosis than wild-type (WT) mice, thus implicating Caspase-11 as a new therapeutic target for preventing or treating COVID-19.
Keywords: SARS–CoV-2; innate immunity; thrombosis.