Host Defense Mechanisms Against Viruses

Crowe, James E.

doi:10.1016/b978-0-323-35214-7.00122-0

Cited by 3 publications

(2 citation statements)

References 403 publications

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“…SARS-CoV-2 infection results in a broad spectrum of clinical manifestations, including both asymptomatic cases and rapid fatalities (Petersen et al, 2020). The activation of the immune system and production of inflammatory cytokines are essential for the natural anti-viral immune responses (Crowe, 2017). However, hyperactivation of the immune system results in an acute increase in circulating levels of pro-inflammatory cytokines, leading to a ''cytokine storm'' (Tisoncik et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Karki

Sharma

Tuladhar

et al. 2021

Cell

1,207

917

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Section: Introductionmentioning

confidence: 99%

Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Karki

Sharma

Tuladhar

et al. 2021

Cell

1,207

917

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“…Cytotoxic CD8þ T cells directly kill virus-infected cells. Through cytokine signalling, CD4þ T cells stimulate B cells directly to produce virus-specific antibodies and to support other defending cell populations indirectly [126,127].…”

Section: Non-human Primatesmentioning

confidence: 99%

The virus that shook the world: questions and answers about SARS-CoV-2 and COVID-19

Alexandrova

Beykov

Vassilev

et al. 2020

Biotechnology & Biotechnological Equipment

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Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes

Karki

Sharma

Tuladhar

et al. 2020

Preprint

189

268

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The COVID-19 pandemic has caused significant morbidity and mortality. Currently, there is a critical shortage of proven treatment options and an urgent need to understand the pathogenesis of multi-organ failure and lung damage. Cytokine storm is associated with severe inflammation and organ damage during COVID-19. However, a detailed molecular pathway defining this cytokine storm is lacking, and gaining mechanistic understanding of how SARS-CoV-2 elicits a hyperactive inflammatory response is critical to develop effective therapeutics. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combined production of TNF-α and IFN-γ specifically induced inflammatory cell death, PANoptosis, characterized by gasdermin-mediated pyroptosis, caspase-8-mediated apoptosis, and MLKL-mediated necroptosis. Deletion of pyroptosis, apoptosis, or necroptosis mediators individually was not sufficient to protect against cell death. However, cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of PANoptosis protected mice from TNF-α and IFN-γ-induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. In vivo neutralization of both TNF-α and IFN-γ in multiple disease models associated with cytokine storm showed that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models, demonstrating the broad physiological relevance of this mechanism. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. The findings also provide a molecular and mechanistic description for the term cytokine storm. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancers where TNF-α and IFN-γ synergism play key pathological roles.

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Host Defense Mechanisms Against Viruses

Cited by 3 publications

References 403 publications

Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

The virus that shook the world: questions and answers about SARS-CoV-2 and COVID-19

Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes

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