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, Rajendra; Sharma, Bhesh Raj; Tuladhar, Shraddha; Williams, Evan P.; Zalduondo, Lillian; Samir, Parimal; Zheng, Min; Sundaram, Balamurugan; Banoth, Balaji; Malireddi, R.K. Subbarao; Schreiner, Patrick; Neale, Geoffrey; Vogel, Peter; Webby, Richard J.; Jonsson, Colleen B.; Kanneganti, Thirumala Devi

doi:10.1016/j.cell.2020.11.025

Cited by 1,200 publications

(1,085 citation statements)

References 133 publications

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“…The cytokine release syndrome (CRS) or cytokine storm is a major cause of acute lung damage associated with patient mortality [38][39][40][41][42][43] . Because the cytokine storm is also common in sepsis caused by other pathogens 42,44 , we determined the mRNA levels of key proinflammatory cytokines and chemokines in the PBMCs of the COV (D1) and ICU cohorts in comparison to the heathy controls.…”

Section: Excessive Jak-stat Signaling Associated With the Cytokine Stormmentioning

confidence: 99%

System-wide hematopoietic and immune signaling aberrations in COVID-19 revealed by deep proteome and phosphoproteome analysis

Kaneko

Esmail

Voss

et al. 2021

Preprint

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The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has become a global crisis. To gain systems-level insights into its pathogenesis, we compared the blood proteome and phosphoproteome of ICU patients with or without SARS-CoV-2 infection, and healthy control subjects by quantitative mass spectrometry. We find that COVID-19 is marked with hyperactive T cell and B cell signaling, compromised innate immune response, and dysregulated inflammation, coagulation, metabolism, RNA splicing, transcription and translation pathways. SARS-CoV-2 infection causes global reprogramming of the kinome and kinase-substrate network, resulting in defective antiviral defense via the CK2-OPN-IL-12/IFN-I axis, lymphocyte cell death via aberrant JAK/STAT signaling, and inactivation of innate immune cells via inhibitory SIRPA, SIGLEC and SLAM family receptor signaling. Our work identifies CK2, SYK, JAK3, TYK2 and IL-12 as potential targets for immunomodulatory treatment of severe COVID-19 and provides a valuable approach and resource for deciphering the mechanism of pathogen-host interactions.

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Section: Excessive Jak-stat Signaling Associated With the Cytokine Stormmentioning

confidence: 99%

System-wide hematopoietic and immune signaling aberrations in COVID-19 revealed by deep proteome and phosphoproteome analysis

Kaneko

Esmail

Voss

et al. 2021

Preprint

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“…While we await understanding of the chief cytokine culprits of severe COVID-19, it might be that broad targeting is more fruitful; murine studies suggest the potential of greater effects of dual cytokine blockade than those of blocking individual cytokines. 9 This is further supported by the evidence, albeit limited, that JAK kinase inhibitors such as baricitinib, which also have a mechanism encompassing blockade of multiple cytokines, can be beneficial for the treatment of COVID-19.…”

mentioning

confidence: 95%

Divergent effects of acute versus chronic glucocorticoids in COVID-19

Robinson

Morand

2021

The Lancet Rheumatology

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Shutterstock Comment e170www.thelancet.com/rheumatology Vol 3 March 2021 risk in patients taking chronic, lower dose glucocorticoids.There is little doubt that even with wide spread vaccination COVID-19 will remain a threat for a subset of patients, potentially including those receiv ing glucocorticoid treatment for autoimmune disease. There fore, it behoves us to continue to investigate and clarify the divergent effects of treatments such as gluco corticoids in order to educate patients and health-care providers.

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“…In conclusion, we identified a novel mechanism of cell signaling integration controlling the transcriptional and proliferative response of regulatory T cells. While this is demonstrated in T cells using only two cytokines, these findings indicate that combinatorial signaling with other cytokines and cell types is possible, and is even beginning to emerge in the literature ( Karki et al, 2021 ). Moreover, while these differences in response may underlie cytokine pleiotropy, they also provide an intriguing guide for new therapeutic applications of combinatorial cytokines in the clinical setting ranging from ex vivo support of autologous cell transfers to immune activation in cancer and inhibition for autoimmunity.…”

Section: Discussionmentioning

confidence: 95%

“…Recently, the global COVID-19 pandemic has brought attention to the devastating effects of cytokine storms, with one study finding that TNFα and IFNγ synergize to trigger inflammatory cell death and increased mortality in SARS-CoV-2 infection ( Karki et al, 2021 ). Mechanistically, previous studies have shown that two cytokines can cooperate by sharing the same STAT proteins to either enhance or interfere with the other to form a different outcome ( Lin and Leonard, 2019 ; Johnston et al, 2012 ; Liao et al, 2011 ), thereby demonstrating the importance of understanding how cytokines may influence each other.…”

Section: Discussionmentioning

confidence: 99%

Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy

Zhou

Álvarez

Cobb

2021

eLife

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Cells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the foundation upon which to better understand the origins of cytokine pleiotropy while informing improved the clinical use of cytokines.

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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

Cited by 1,200 publications

References 133 publications

System-wide hematopoietic and immune signaling aberrations in COVID-19 revealed by deep proteome and phosphoproteome analysis

System-wide hematopoietic and immune signaling aberrations in COVID-19 revealed by deep proteome and phosphoproteome analysis

Divergent effects of acute versus chronic glucocorticoids in COVID-19

Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy

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