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10.1073/pnas.2202012119 http://scihub22266oqcxt.onion/10.1073/pnas.2202012119 35588457!9173818!35588457     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\35588457.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Proc+Natl+Acad+Sci+U+S+A 2022 ; 119 (21): e2202012119 Nephropedia Template TP {{tp|p=35588457|t=2022. Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis |pdf=|usr=}}{{35588457}} gab.com Text Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis JO: Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=35588457 #FOAvip 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)-1beta, 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. Twit Text FOAVip Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis ????Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=35588457 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=35588457 #FOAvip English Wikipedia <ref>{{Cite pmid|35588457}}</ref> Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis #MMPMID35588457 Eltobgy MM; Zani A; Kenney AD; Estfanous S; Kim E; Badr A; Carafice C; Daily K; Whitham O; Pietrzak M; Webb A; Kawahara J; Eddy AC; Denz P; Lu M; Kc M; Peeples ME; Li J; Zhu J; Que J; Robinson R; Rosas Mejia O; Rayner RE; Hall-Stoodley L; Seveau S; Gavrilin MA; Zhang X; Thomas J; Kohlmeier JE; Suthar MS; Oltz E; Tedeschi A; Robledo-Avila FH; Partida-Sanchez S; Hemann EA; Abdelrazik E; Forero A; Nimjee SM; Boyaka PN; Cormet-Boyaka E; Yount JS; Amer AO Proc Natl Acad Sci U S A 2022[May]; 119 (21): e2202012119 PMID35588457show ga 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)-1beta, 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. |*COVID-19/enzymology/pathology[MESH] |*SARS-CoV-2[MESH] |*Thromboinflammation/enzymology/genetics[MESH] |Animals[MESH] |Caspases, Initiator/genetics/*metabolism[MESH] |Disease Progression[MESH] |Humans[MESH] |Lung/pathology[MESH] |Mice[MESH] |Mice, Knockout[MESH]Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by p(epmc).pdf DeepDyve Pubget Overpricing