Caspase-4/11 exacerbates disease severity in SARS–CoV-2 infection by promoting inflammation and immunothrombosis
Eltobgy, Mostafa M.; Zani, Ashley; Kenney, Adam D.; Estfanous, Shady; Kim, Eunsoo; Badr, Asmaa; Carafice, Cierra; Daily, Kylene; Whitham, Owen; Pietrzak, Maciej; Webb, Amy; Kawahara, Jeffrey; Eddy, Adrian C.; Denz, Parker; Lu, Mijia; KC, Mahesh; Peeples, Mark E.; Li, Jianrong; Zhu, Jian; Que, Jianwen; Robinson, Richard; Rosas Mejia, Oscar; Rayner, Rachael E.; Hall-Stoodley, Luanne; Seveau, Stephanie; Gavrilin, Mikhail A.; Zhang, Xiaoli; Thomas, Jeronay; Kohlmeier, Jacob E.; Suthar, Mehul S.; Oltz, Eugene; Tedeschi, Andrea; Robledo-Avila, Frank H.; Partida-Sanchez, Santiago; Hemann, Emily A.; Abdelrazik, Eman; Forero, Adriana; Nimjee, Shahid M.; Boyaka, Prosper N.; Cormet-Boyaka, Estelle; Yount, Jacob S.; Amer, Amal O.
SIGNIFICANCE
We 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.
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS–CoV-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 SARS–CoV-2 infections and that CASP4 expression correlates with severity of SARS–CoV-2 infection in humans.
SARS–CoV-2–infected 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 SARS–CoV-2–infected 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)-1β, 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 SARS–CoV-2–induced inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.
Link | PDF (Proceedings of the National Academy of Sciences) [Open Access]
Eltobgy, Mostafa M.; Zani, Ashley; Kenney, Adam D.; Estfanous, Shady; Kim, Eunsoo; Badr, Asmaa; Carafice, Cierra; Daily, Kylene; Whitham, Owen; Pietrzak, Maciej; Webb, Amy; Kawahara, Jeffrey; Eddy, Adrian C.; Denz, Parker; Lu, Mijia; KC, Mahesh; Peeples, Mark E.; Li, Jianrong; Zhu, Jian; Que, Jianwen; Robinson, Richard; Rosas Mejia, Oscar; Rayner, Rachael E.; Hall-Stoodley, Luanne; Seveau, Stephanie; Gavrilin, Mikhail A.; Zhang, Xiaoli; Thomas, Jeronay; Kohlmeier, Jacob E.; Suthar, Mehul S.; Oltz, Eugene; Tedeschi, Andrea; Robledo-Avila, Frank H.; Partida-Sanchez, Santiago; Hemann, Emily A.; Abdelrazik, Eman; Forero, Adriana; Nimjee, Shahid M.; Boyaka, Prosper N.; Cormet-Boyaka, Estelle; Yount, Jacob S.; Amer, Amal O.
SIGNIFICANCE
We 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.
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS–CoV-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 SARS–CoV-2 infections and that CASP4 expression correlates with severity of SARS–CoV-2 infection in humans.
SARS–CoV-2–infected 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 SARS–CoV-2–infected 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)-1β, 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 SARS–CoV-2–induced inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.
Link | PDF (Proceedings of the National Academy of Sciences) [Open Access]