Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis.
Proc Natl Acad Sci U S A
; 119(21): e2202012119, 2022 05 24.
Статья
в английский
| MEDLINE | ID: covidwho-1852638
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is a worldwide health concern, and new treatment strategies are needed. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4) and its mouse homolog, caspase-11 (CASP11), are up-regulated in SARSCoV-2 infections and that CASP4 expression correlates with severity of SARSCoV-2 infection in humans. SARSCoV-2infected Casp11−/− mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) mice and mice lacking the caspase downstream effector gasdermin-D (Gsdmd−/−). Notably, viral titers were similar regardless of CASP11 knockout. Global transcriptomics of SARSCoV-2infected WT, Casp11−/−, and Gsdmd−/− lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11−/− mice. We confirmed that protein levels of inflammatory mediators interleukin (IL)-1ß, IL-6, and CXCL1, as well as neutrophil functions, were reduced in Casp11−/− lungs. Additionally, Casp11−/− lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11 promotes detrimental SARSCoV-2induced inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.
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Полный текст:
Имеется в наличии
Коллекция:
Международные базы данных
база данных:
MEDLINE
Основная тема:
Caspases, Initiator
/
SARS-CoV-2
/
COVID-19
/
Thromboinflammation
Тип исследования:
Прогностическое исследование
Пределы темы:
Животные
/
Люди
Язык:
английский
Журнал:
Proc Natl Acad Sci U S A
Год:
2022
Тип:
Статья
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