Caspase-11 promotes inflammation and thrombosis in SARS-CoV-2 infection
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ABSTRACT:
PROVIDER: PRJNA765615 | ENA |
REPOSITORIES: ENA
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Project description:SARS-CoV-2 infections are a worldwide health concern, and new treatment strategies are needed for decreasing virus-induced inflammatory tissue damage. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that the innate immunity proteins, human caspase-4 (CASP4), and its mouse homologue, caspase-11 (CASP11), are upregulated 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 experienced less severe infections in terms of weight loss and lung damage than WT mice. Notably, these phenotypes were not recapitulated in mice lacking the CASP11 downstream effector gasdermin D (Gsdmd-/-), though viral titers were similar in all groups. Global transcriptomics of infected WT and Casp11-/- lungs identified decreased inflammation and neutrophil gene signatures. We confirmed that protein levels of inflammatory mediators IL-1β and CXCL1, and neutrophil infiltration, were decreased in Casp11-/- lungs. Additionally, Casp11-/- lungs expressed less von Willebrand factor, a marker for endothelial dysfunction and more Kruppel-Like Factor 2 (KLF2), a transcription factor with anti-thrombotic functions. Thus, CASP11 is established as an upstream regulator of blood coagulopathy in SARS-CoV-2 infection. Overall, our results demonstrate that CASP11, promotes detrimental SARS-CoV-2-associated inflammation and coagulopathy, identifying CASP11 as a promising drug target for treatment and prevention of tissue damage in COVID-19.
2023-02-16 | GSE184678 | GEO
Project description:The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details that underlie these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular and cellular pathways associated with SARS-CoV-2 pathogenesis, we performed transcriptomic analyses of bronchoalveolar lavage (BAL) samples and peripheral blood, and proteomics analyses of serum from infected rhesus macaques. We observed upregulation of macrophage signatures, complement cascade pathways, platelet activation, and markers of thrombosis in BAL and peripheral blood as well as extensive macrophage infiltrates in lung. These observations coincided with robust induction of interferon and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFa and NF-κB as well as downstream signaling pathways. These findings suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2 induced vascular disease. Our findings also suggest potential novel therapeutic targets for COVID-19 disease.
2020-10-20 | GSE156701 | GEO
Project description:Ad26.COV2.S Prevents SARS-CoV-2 Induced Pathways of Inflammation and Thrombosis in Hamsters
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Project description:Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease, and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 challenge in hamsters stimulates myeloid and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, single-dose immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways such that the gene expression profiles of vaccinated hamsters are comparable to uninfected animals. Furthermore, we validated the protective efficacy of the Ad26.COV2.S against proinflammatory pathways and coagulation cascade in rhesus macaques by proteomics. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses. These data provide further insights into the mechanisms of Ad26.COV2.S based protection against severe COVID-19 in hamsters.
2022-03-26 | GSE196893 | GEO
Project description:To determine the transcriptional effects of caspase 1 and caspase 11 deficiency as well as Emu-myc, we performed RNA sequencing (RNAseq) on sorted HSCs from four groups of mice (wild type, Emu-myc, Casp1−⁄−Casp11−⁄−, and Casp1−⁄−Casp11−⁄−Emu-myc).
2024-06-01 | GSE183695 | GEO
Project description:Gut microbiota contributes to the regulation of host immune response and homeostasis. Bile acid (BA) derivatives from gut microbiota can affect the differentiation and function of the immune cells. However, it is incompletely clear for the regulation of BA metabolites in the macrophages. We here find that BA metabolites can regulate sensitivity of macrophages to LPS and or Gram-negative bacteria. BA derivatives could induce lncRNA57RIK expression through sphingosine-1-phosphate receptor 2 (S1PR2) in the macrophages of mice and humans, which play a critical role in Gram-negative bacteria mediated IL-1β maturation and pyroptosis of macrophages. This lncRNA57RIK could bind intracellular proteases caspase-4/11 with guanylate-binding protein 1 (GBP1) in the human and mice together to cause LPS mediated activation of caspase-4/11. Murine or human lncRNA57RIK knockout (KO) macrophages did not produce response(s) to LPS or gram negative bacteria. LncRNA57RIK KO mice had also reduced inflammatory responses to LPS or Salmonella typhimurium (S.T) infection. Taken together, gut microbiota derived BA metabolites mediated lncRNA57RIK is necessary for LPS induced caspase-4/11 activation.
2024-09-21 | GSE277195 | GEO
Project description:Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation
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Project description: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.
| S-EPMC9173818 | biostudies-literature
Project description:Caspase-1 activation senses metabolic danger-associated molecular patterns and mediates the initiation of inflammation. Here, we reported that caspase-1 contributes to hyperlipidemia-induced modulation of vascular cell gene expression during early atherosclerosis in vivo. Our results demonstrate the therapeutic potential of caspase-1 inhibition in the treatment of cardiovascular diseases. All mice were in a C57B/L6 strain background. Male wild-type mice, Apolipoprotein E (ApoE) gene knockout mice, and ApoE/Caspase-1 double gene deficient mice were fed with high fat diet for 3 weeks starting from 8 weeks to induce early dyslipidemia. At 11-week of age, aortas from these mice were used for microarray analysis. 5 biological replicates in each group.
2015-08-21 | E-GEOD-72248 | biostudies-arrayexpress
Project description:Patients diagnosed with coronavirus disease 2019 (COVID-19) mostly become critically ill around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces hyper-inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the Fc tail. Notably, low anti-spike IgG fucosylation normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the hyper-inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of the kinase, Syk.
2021-04-30 | E-MTAB-10431 | biostudies-arrayexpress