Caspase-4/11 exacerbates disease severity in SARS–CoV-2 infection by promoting inflammation and immunothrombosis

Eltobgy, Mostafa; 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.; Lǐ, Jiànróng; Zhu, Jian; Que, Jianwen; Robinson, Richard; Mejia, Oscar Rosas; Rayner, Rachael E.; Hall-Stoodley, Luanne; Seveau, Stéphanie; Gavrilin, Mikhail A.; Zhang, Xiaoli; Thomas, J.; Kohlmeier, Jacob E.; Suthar, Mehul S.; Oltz, Eugene M.; Tedeschi, Andrea; Robledo‐Avila, Frank; Partida-Sánchez, Santiago; Hemann, Emily A.; Abdelrazik, Eman; Forero, Adriana; Nimjee, Shahid M; Boyaka, Prosper N.; Cormet‐Boyaka, Estelle; Yount, Jacob S.; Amer, Amal O.

doi:10.1073/pnas.2202012119

Cited by 29 publications

(19 citation statements)

References 57 publications

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“…Either CASP4/11 has a positive and a negative effect in viral replication and they neutralize each other or CASP4/11 activation does not influence any biological process involved in SARS-CoV-2 replication in tissues. It is worth mentioning that these findings were consistent with a recently published study, where the authors show a role of CASP4/11 in disease aggravation, but not in viral replication (Eltobgy et al, 2022). Importantly, the fact that CASP4/11 ablation does not increase viral replication in tissues provides relevant information to endorse further exploitation of drugs that target CASP4 in COVID-19 patients.…”

Section: Discussionsupporting

confidence: 92%

“…(1:200, MBL, M029-3). The Sequential Immunoperoxidase Labeling and Erasing (SIMPLE) technique was used to evaluate all markers in the same tissue (Glass et al, 2009). After incubation with primary antibody, slides were incubated with immune peroxidase polymer anti-mouse visualization system (SPD-125, Spring Bioscience, 345 Biogen) and with chromogen-substrate AEC peroxidase system kit (SK-4200, 346 Vector Laboratories, Burlingame, CA).…”

Section: Sequential Immunoperoxidase Labeling and Erasingmentioning

confidence: 99%

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CASP4/11 contributes to pulmonary inflammation and disease exacerbation in COVID-19

Rodrigues

Caetano

et al. 2022

Preprint

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Infection with SARS-CoV-2 induces COVID-19, an inflammatory disease that is usually self-limited, but depending on patient conditions may culminate with critical illness and patient death. The virus triggers activation of intracellular sensors, such as the NLRP3 inflammasome, which promotes inflammation and aggravates the disease. Thus, identification of host components associated with NLRP3 inflammasome is key for understanding the physiopathology of the disease. Here, we reported that SARS-CoV-2 induces upregulation and activation of human Caspase-4/CASP4 (mouse Caspase-11/CASP11) and this process contributes to inflammasome activation in response to SARS-CoV-2. CASP4 was expressed in lung autopsy of lethal cases of COVID-19 and CASP4 expression correlates with expression of inflammasome components and inflammatory mediators such as CASP1, IL1B, IL18 and IL6. In vivo infections performed in transgenic hACE2 humanized mouse, deficient or sufficient for Casp11, indicate that hACE2 Casp11-/- mice were protected from disease development, with reduced body weight loss, reduced temperature variation, increased pulmonary parenchymal area, reduced clinical score of the disease and reduced mortality. Collectively, our data establishes that CASP4/11 contributes to disease pathology and contributes for future immunomodulatory therapeutic interventions to COVID-19.

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Section: Discussionsupporting

confidence: 92%

Section: Sequential Immunoperoxidase Labeling and Erasingmentioning

confidence: 99%

CASP4/11 contributes to pulmonary inflammation and disease exacerbation in COVID-19

Rodrigues

Caetano

et al. 2022

Preprint

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“…Additionally, during SARS-CoV-2 infection, the expression of proteins involved in non-canonical NLRP3 inflammasome signaling, through caspase-11 and caspase-4, are upregulated in the lungs of mice and humans, respectively. Deficiency of caspase-11, but not GSDMD, an executioner of pyroptosis, reduces disease severity in SARS-CoV-2–infected mice [ 66 ], suggesting that caspase-11 (or caspase-4/5 in humans) may promote disease severity in COVID-19 independently of pyroptosis. Caspase-4/11 can be activated by oxidized phospholipids that are produced in damaged tissues (Fig.…”

Section: Innate Immune Sensing and Signaling In Response To Sars-cov-2mentioning

confidence: 99%

Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Karki

Kanneganti

2022

J Transl Med

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The innate immune system serves as the first line of defense against invading pathogens; however, dysregulated innate immune responses can induce aberrant inflammation that is detrimental to the host. Therefore, careful innate immune regulation is critical during infections. The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in global morbidity and mortality as well as socio-economic stresses. Innate immune sensing of SARS-CoV-2 by multiple host cell pattern recognition receptors leads to the production of various pro-inflammatory cytokines and the induction of inflammatory cell death. These processes can contribute to cytokine storm, tissue damage, and acute respiratory distress syndrome. Here, we discuss the sensing of SARS-CoV-2 to induce innate immune activation and the contribution of this innate immune signaling in the development and severity of COVID-19. In addition, we provide a conceptual framework for innate immunity driving cytokine storm and organ damage in patients with severe COVID-19. A better understanding of the molecular mechanisms regulated by innate immunity is needed for the development of targeted modalities that can improve patient outcomes by mitigating severe disease.

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“…Indeed, IAV is known to trigger multiple inflammatory pathways, including the activation of cellular inflammasomes through multiple mechanisms 3 . However, whether inflammasome activation is beneficial or detrimental to the outcome of infection is a topic of debate [4][5][6][7][8][9] . Further, roles for many of the specific effector proteins downstream of inflammasome activation remain unstudied during influenza virus infection.…”

Section: Introductionmentioning

confidence: 99%

Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation

Speaks

Zani

Solstad

et al. 2023

Preprint

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Influenza A virus activates cellular inflammasome pathways, though it remains unknown whether many of the effector proteins downstream of inflammasome activation promote virus clearance or instead promote pathological inflammation. We investigated the role of gasdermin D (GSDMD), a pore-forming inflammasome effector protein that allows cellular release of inflammatory molecules and eventual pyroptotic lysis of cells. GSDMD knockout (KO) mice infected with influenza virus exhibited reduced weight loss and mortality compared to infected wild type (WT) mice. Lung viral titers were similar between genotypes, indicating that GSDMD does not directly affect virus replication. Instead, we observed that GSDMD KO mice had less severe lung inflammation, histopathology, and immune cell infiltration, suggesting that GSDMD promotes tissue-damaging immune responses following infection. Global transcriptomic analysis revealed significant decreases in specific inflammatory gene programs in GSDMD KO lungs, including decreased neutrophil chemotaxis and activation gene signatures, which were confirmed by decreased neutrophil elastase measurements and decreased neutrophil numbers in the lung. Indeed, exogenous depletion of neutrophils starting at day 3 post infection in WT mice recapitulated the protective phenotype observed in GSDMD KO mice, implicating neutrophils as central players in the GSDMD-dependent pathological response to influenza virus. Overall, these findings reveal an important role for GSDMD during influenza virus-induced lung inflammation, pathogenesis, and neutrophil accumulation. Therapeutic interventions targeting the GSDMD/neutrophil axis may provide an effective means to treat severe influenza virus infection.

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Caspase-4/11 exacerbates disease severity in SARS–CoV-2 infection by promoting inflammation and immunothrombosis

Cited by 29 publications

References 57 publications

CASP4/11 contributes to pulmonary inflammation and disease exacerbation in COVID-19

CASP4/11 contributes to pulmonary inflammation and disease exacerbation in COVID-19

Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation

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