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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (14)

NSP5 (4)

ProteinS1 (3)

ProteinN (2)

NSP2 (1)


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SARS-CoV-2 Proteins
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    SARS-CoV-2 spike PROTEIN glycoprotein S1 induces neuroinflammation in BV-2 microglia

    Authors: Olumayokun A Olajide; Victoria U Iwuanyanwu; Oyinkansola D Adegbola; Oliver Artz; Daniele Rosado; Tara Skopelitis; Munenori Kitagawa; Ullas V Pedmale; David Jackson

    doi:10.1101/2020.12.29.424619 Date: 2020-12-29 Source: bioRxiv

    The emergence of SARS-CoV-2 has resulted in a global pandemic. In addition to respiratory complications as a result of SARS-CoV-2 illness MESHD, accumulating evidence suggests that neurological and neuropsychiatric symptoms MESHD are associated with the disease caused by the virus. In this study, we investigated the effects of the SARS-CoV-2 spike PROTEIN glycoprotein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNF HGNC, IL-6 HGNC, IL-1{beta HGNC} and iNOS HGNC/NO. SARS-CoV-2 spike PROTEIN glycoprotein S1 increased protein expressions of phospho-p65 and phospho-I{kappa}B, as well as enhancing DNA binding and transcriptional activity of NF-{kappa}B HGNC. Pro-inflammatory effects of the glycoprotein effects were reduced in the presence of BAY11-7082 (1 M). The presence of SARS-CoV-2 spike PROTEIN glycoprotein S1 in BV-2 microglia increased the protein expression of NLRP3 HGNC, as well as caspase-1 HGNC activity. However, pre-treatment with CRID3 (1 M) or BAY11-7082 (1 M) resulted in the inhibition of NLRP3 HGNC inflammasome/ caspase-1 HGNC. It was also observed that CRID3 attenuated SARS-CoV-2 spike PROTEIN glycoprotein S1-induced increase in IL-1{beta HGNC} production. Increased protein expression of p38 MAPK was observed in BV-2 microglia stimulated with the spike glycoprotein S1 PROTEIN, and was reduced in the presence of SKF 86002. These results have provided the first evidence demonstrating SARS-CoV-2 spike PROTEIN S1 glycoprotein-induced neuroinflammation in BV-2 microglia. We propose that promotion of neuroinflammation by this glycoprotein is mediated through activation of NF-{kappa}B HGNC, NLRP3 HGNC inflammasome and p38 MAPK. These results are significant because of their relevance to our understanding of neurological and neuropsychiatric symptoms MESHD observed in patients infected with SARS-CoV-2.

    Kinetics of Plasma Cytokines During and After Two Different Modalities of Extracorporeal Blood Purification in Critically Ill COVID-19 MESHD Patients

    Authors: Daniela Ponce; Welder Zamoner; Luis Eduardo Magalhães; Paula Gabriela Souza de Oliveira; Patricia Polla; Alexandre Naime Barbosa; Marjorie de Assis Golim; Andre Luis Balbi

    doi:10.21203/rs.3.rs-136018/v1 Date: 2020-12-25 Source: ResearchSquare

    Cytokine storm syndrome ( CSS MESHD) has been documented in coronavirus disease 2019 MESHD ( COVID-19 MESHD) since the first reports of this disease. In the absence of vaccines or direct therapy for COVID-19 MESHD, extracorporeal blood treatment (EBT) could represent an option for the removal of cytokines and may be beneficial to improve the clinical outcome of critically ill MESHD patients. Intermittent haemodialysis ( IHD MESHD), using high flux (HF) or high cut-off membranes, and continuous renal replacement therapy (CRRT) could be used for blood purification in COVID-19 MESHD patients with CSS. To the best of our knowledge, cytokine kinetics during and after different types of EBT on COVID-19 MESHD patients have never been studied. In this study, we describe cytokine variation and removal during and after IHD MESHD and CRRT in COVID-19 MESHD patients with acute kidney injury MESHD ( AKI MESHD). Methods: Patients with COVID-19 MESHD-related AKI MESHD according to Kidney Disease MESHD Improving Global Outcomes (KDIGO) criteria and admitted at Intensive Care Unit (ICU) were studied. Blood samples were collected at the start and end of both IHD MESHD using HF membranes (10 patients) and continuous venovenous haemodiafiltration (CVVHDF: 10 patients) in two sessions for measuring 13 different plasma interleukins and calculating the cytokine removal rate. Results: We evaluated cytokine removal in patients with COVID-19 MESHD-related AKI MESHD undergoing either prolonged IHD MESHD (10 patients) or CRRT (CVVHDF: 10 patients). There was no difference between the IHD MESHD and CVVHDF groups regarding mechanical ventilation, vasoactive drug use, age or prognostic scores. Patients treated by CRRT presented higher levels of IL-2 HGNC and IL-8 HGNC than patients treated by prolonged IHD at the start of dialysis. Cytokine removal ranged from 9–78%. Patients treated by CRRT presented higher cytokine removal rates than those treated by prolonged IHD for IL-2 HGNC, IL-6 IL-8, IP-10 HGNC and TNF HGNC. The removal rates of IL-4 HGNC, IL-10 HGNC, IL-1β HGNC, IL-17A HGNC, IFN HGNC, MCP-1 HGNC and free active TGF-B1 HGNC were similar in the two groups. After one session of CVVHDF (24 h) the IL-2 HGNC and IL-1β HGNC levels did not vary significantly, whereas IL-4 HGNC, IL-6 HGNC, IL-8 HGNC, IL-10 HGNC, IL-17A HGNC, TNF HGNC, IFN HGNC, IP-10 HGNC, MCP-1 HGNC, IL-12p70 and free active TGF-B1 HGNC decreased by 33.8–76%, and this decrease was maintained over the next 24 h. In the prolonged IHD groups, IL-2 HGNC, IL-6 HGNC, TNF HGNC, IP-10 HGNC and IL-1β HGNC levels did not decrease significantly whereas IL-4 HGNC, IL-8 HGNC, IL-10 HGNC, IL-17A HGNC, IFN HGNC, MCP-1 HGNC, IL-12p70 and free active TGF-B1 HGNC decreased by 21.8–72%. However, all cytokine levels returned to their initial values after 24 h, despite their removal. Conclusions: Cytokine removal is lower using prolonged IHD MESHD with HF membranes than by using CVVHDF, and IHD MESHD allows a transient and selective decrease in cytokines that can be correlated with mortality during CSS-related COVID-19 MESHD.

    Altered Transcript Levels of Cytokines in COVID-19 MESHD Patients

    Authors: Majid Samsami; Alireza Fatemi; Reza Jalili Khoshnoud; Karim Kohansal; Arezou Sayad; Shabnam Soghala; Shahram Arsang-Jang; Mohammad Taheri; Soudeh Ghafouri-Fard

    doi:10.21203/rs.3.rs-126215/v1 Date: 2020-12-10 Source: ResearchSquare

    The pandemic caused by severe acute respiratory syndrome coronavirus 2 MESHD and the related disorder i.e. “ coronavirus disease 2019 MESHD” ( COVID-19 MESHD) have encouraged researchers to unravel the molecular mechanism of disease severity. Several lines of evidence support the impact of "cytokine storm" in the pathogenesis of severe forms of the disorder MESHD. We aimed to assess the expression levels of nine cytokine coding in COVID-19 MESHD patients admitted in a hospital. Expression levels of IFN-G HGNC, IL-2 HGNC, IL-4 HGNC, IL-6 HGNC, IL-17 HGNC, TGF-B HGNC, IL-8 HGNC and IL-1B HGNC were significantly higher in COVID-19 MESHD patients compared with healthy controls and in both female and male patients compared with sex-matched controls. However, expression of none of these cytokines was different between ICU-admitted patients and other patients except for IL-6 HGNC whose expression was lower in the former group compared with the latter (ratio of means = 0.33, P value = 4.82E-02). Expression of TNF-A HGNC was not different between COVID-19 MESHD patients and healthy controls. Then, we assessed diagnostic power of cytokine coding genes in differentiating between COVID-19 MESHD patients and controls. The area under curve (AUC) values range from 0.94 for IFN-G HGNC to 1.0 for IL-2 HGNC and IL-1B HGNC. After combining the transcript levels of all cytokines, AUC, sensitivity and specificity values reached 1.0, 1.0 and 0.99, respectively. For differentiation between ICU-admitted patients and other patients, IL-4 HGNC with AUC value of 0.68, had the best diagnostic power among cytokine coding genes. Expression of none of cytokine coding genes was correlated with the assessed clinical/demographic data including age, gender, ICU admission, or CRP HGNC/ESR levels. Our study provides further evidence for contribution of “cytokine storm” in the pathobiology of moderate/severe forms of COVID-19 MESHD.

    Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection MESHD

    Authors: Nina Le Bert; Hannah E Clapham; Anthony T Tan; Wan Ni Chia; Christine YL Tham; Jane M Lim; Kamini Kunasegaran; Linda Tan; Charles-Antoine Dutertre; Nivedita Shankar; Joey ME Lim; Louisa Jin Sun; Marina Zahari; Zaw M Tun; Vishakha Kumar; Beng Lee Lim; Siew Hoon Lim; Adeline Chia; Yee-Joo Tan; Paul Anantharajah Tambyah; Shirin Kalimuddin; David CB Lye; Jenny GH Low; Lin-Fa Wang; Wei Yee Wan; Li Yang Hsu; Antonio Bertoletti; Clarence C Tam; Martina Recalde; Paula Casajust; Jitendra Jonnagaddala; Vignesh Subbian; David Vizcaya; Lana YH Lai; Fredrik Nyberg; Daniel R. Morales; Jose D. Posada; Nigam H. Shah; Mengchun Gong; Arani Vivekanantham; Aaron Abend; Evan P Minty; Marc A. Suchard; Peter Rijnbeek; Patrick B Ryan; Daniel Prieto-Alhambra

    doi:10.1101/2020.11.25.399139 Date: 2020-11-27 Source: bioRxiv

    The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between their antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 infection MESHD without symptoms or disease could reveal non-pathological yet protective characteristics. We therefore compared the quantity and function of SARS-CoV-2-specific T cells in a cohort of asymptomatic individuals (n=85) with that of symptomatic COVID-19 MESHD patients (n=76), at different time points after antibody seroconversion. We quantified T cells reactive to structural proteins (M PROTEIN, NP and Spike) using ELISpot assays, and measured the magnitude of cytokine secretion ( IL-2 HGNC, IFN-{gamma HGNC}, IL-4 HGNC, IL-6 HGNC, IL-1{beta}, TNF- and IL-10) in whole blood following T cell activation with SARS-CoV-2 peptide pools as a functional readout. Frequencies of T cells specific for the different SARS-CoV-2 proteins in the early phases of recovery were similar between asymptomatic and symptomatic individuals. However, we detected an increased IFN-{gamma HGNC} and IL-2 HGNC production in asymptomatic compared to symptomatic individuals after activation of SARS-CoV-2-specific T cells in blood. This was associated with a proportional secretion of IL-10 HGNC and pro-inflammatory cytokines ( IL-6 HGNC, TNF HGNC- and IL-1{beta} HGNC) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2 infected MESHD individuals are not characterized by a weak antiviral immunity; on the contrary, they mount a robust and highly functional virus-specific cellular immune response. Their ability to induce a proportionate production of IL-10 HGNC might help to reduce inflammatory events during viral clearance.

    Preparing for the Storm: Mitigating the Effect of SARS-CoV-2 Induced Hypercytokinemia

    Authors: Adekunle Rowaiye; Okiemute Okpalefe; Olukemi Onuh; Joyce Ogidigo; Oluwakemi Oladipo; Amoge Ogu; Angus Oli; Samson Olofinase; Onyekachi Onyekwere

    id:10.20944/preprints202011.0604.v1 Date: 2020-11-24 Source: Preprints.org

    With increasing fatalities, the COVID-19 pandemic MESHD COVID-19 pandemic MESHD constitutes a formidable global health challenge. The causative agent, SARS-CoV-2 constantly tests the efficacy of the immune system of its victims. The protective ability of the innate immune system as the first responder largely determines the progression of disease and its clinical prognosis. Evidence suggests that mortalities associated with COVID-19 MESHD are largely due to hyperinflammation and a dysregulated immune response. Consequently, the degree of the release of pro-inflammatory cytokines such as IL1 HGNC, IL-6 HGNC, and TNF alpha HGNC remarkably distinguishes between mild and severe cases of COVID-19 MESHD. The early prediction of a cytokine storm is made possible by several serum chemistry and hematological markers. The prompt use of these markers for laboratory tests, and the aggressive prevention and management of a cytokine release syndrome is critical in determining the level of morbidity and fatality associated with COVID-19 MESHD. With respect to the SARS-CoV-2 and the host cell, this literature review focuses on the dynamics of the COVID-19 MESHD disease highlighting on the pathogenesis, and the markers of Cytokine Storm. It also proffers solutions by critically looking at the current and potential pharmacological agents that are or can be used to mitigate and manage cytokine storms.

    Transcriptome Profiling of different types of human respiratory tract cells infected by SARS-CoV-2 Highlight an unique Role for Inflammatory and Interferon Response

    Authors: Luping Lei; Qiumei Cao; Yu Wang; Mario Hensen; Anu V. Chandran; Michelle L. Hill; J.L. Kiappes; Raymond A. Dwek; Dominic S. Alonzi; Weston B. Struwe; Nicole Zitzmann; Florian M Wurm; Xin Zheng; Jia Liu; Davey Smith; Daniela Weiskopf; Alessandro Sette; Shane Crotty; Jian Jin; Xian Chen; Andrew Pekosz; Sabra Klein; Irina Burd

    doi:10.1101/2020.11.15.383927 Date: 2020-11-16 Source: bioRxiv

    The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease MESHD ( COVID-19 MESHD) at the end of 2019 has caused a large global outbreak and now become a major public health issue. Lack of data underlying how the human host interacts with SARS-CoV-2 virus. In the current study, We performed Venn-analysis, Gene ontology (GO), KEGG pathway analysis and Protein-protein interaction analysis of whole transcriptome studies with the aim of clarifying the genes and pathways potentially altered during human respiratory tract cells infected with SARS-CoV-2. We selected four studies through a systematic search of the Gene Expression Omnibus (GEO) database or published article about SARS-CoV-2 infection MESHD in different types of respiratory tract cells. We found 36 overlapping upregulated genes among different types of cells after viral infection. Further functional enrichment analysis revealed these DEGs are most likely involved in biological processes related to inflammatory response and response to cytokine, cell component related to extracellular space and I-kappaB/NF-kappaB complex, molecular function related to protein binding and cytokine activity. KEGG pathways analysis highlighted altered conical and casual pathways related to TNF HGNC, NF-kappa B HGNC, Cytokine-cytokine receptor interaction and IL17 HGNC signaling pathways during SARS-CoV-2 infection MESHD with CXCL1 HGNC, CXCL2 HGNC, CXCL3 HGNC, CXCL8 HGNC, CXCL10 HGNC, IL32 HGNC, CX3CL1 HGNC, CCL20 HGNC, IRF1 HGNC, NFKB2 HGNC and NFKB1A up-regulated which may explain the inflammatory cytokine storms associated with severe cases of COVID-19 MESHD.

    Kinetics of viral load, immunological mediators and characterization 1 of a SARS-CoV-2 isolate in mild COVID-19 MESHD patients during acute phase of infection

    Authors: Anbalagan Anantharaj; Suni Gujjar; Saurabh Kumar; Nikhil Verma; Jigme Wangchuk; Naseem Ahmed Khan; Aleksha Panwar; Akshay Kanakan; Vivekanand A; Janani Srinivasa Vasudevan; Asim Das; Anil Kumar Pandey; Rajesh Pandey; Guruprasad R Medigeshi

    doi:10.1101/2020.11.05.20226621 Date: 2020-11-07 Source: medRxiv

    Over 95% of the COVID-19 MESHD cases are mild-to-asymptomatic who contribute to disease transmission whereas most of the severe manifestations of the disease are observed in elderly and in patients with comorbidities and dysregulation of immune response has been implicated in severe clinical outcomes. However, it is unclear whether asymptomatic or mild infections are due to low viral load or lack of inflammation MESHD. We have measured the kinetics of SARS-CoV-2 viral load in the respiratory samples and serum markers of inflammation MESHD in hospitalized COVID-19 MESHD patients with mild symptoms. We observed a bi-phasic pattern of virus load which was eventually cleared in most patients at the time of discharge. Viral load in saliva samples from a subset of patients showed good correlation with nasopharyngeal samples. Serum interferon levels were downregulated during early stages of infection but peaked at later stages correlating with elevated levels of T-cell cytokines and other inflammatory mediators such as IL-6 HGNC and TNF-alpha HGNC which showed a bi-phasic pattern. The clinical recovery of patients correlated with decrease in viral load and increase in interferons and other cytokines which indicates an effective innate and adaptive immune function in mild infections. We further characterized one of the SARS-CoV-2 isolate by plaque purification and show that infection of lung epithelial cells (Calu-3) with this isolate led to cytopathic effect disrupting epithelial barrier function and tight junctions. Finally we showed that zinc was capable of inhibiting SARS-CoV-2 infection MESHD in this model suggesting a beneficial effect of zinc supplementation in COVID-19 MESHD infection.

    SLAMF7 HGNC engagement super-activates macrophages in acute and chronic inflammation

    Authors: Accelerating Medicines Partnership (AMP) RA/SLE Network; Andrew Howe; James B Gilchrist; Dapeng Sun; Michael Knight; Laura C Zanetti-Domingues; Benji Bateman; Anna-Sophia Krebs; Long Chen; Julika Radecke; Yuewen Sheng; Vivian D Li; Tao Ni; Ilias Kounatidis; Mohamed A Koronfel; Marta Szynkiewicz; Maria Harkiolaki; Marisa L Martin-Fernandez; William James; Peijun Zhang

    doi:10.1101/2020.11.05.368647 Date: 2020-11-05 Source: bioRxiv

    Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation MESHD. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 HGNC as a receptor associated with a super-activated macrophage state in rheumatoid arthritis MESHD. We implicated IFN-gamma HGNC as a key regulator of SLAMF7 HGNC expression. Engaging this receptor drove an exuberant wave of inflammatory cytokine expression, and induction of TNF-alpha HGNC following SLAMF7 HGNC engagement amplified inflammation MESHD through an autocrine signaling loop. We observed SLAMF7 HGNC-induced gene programs not only in macrophages from rheumatoid arthritis MESHD patients, but in gut macrophages from active Crohn's disease MESHD patients and lung macrophages from severe COVID-19 MESHD patients. This suggests a central role for SLAMF7 HGNC in macrophage super-activation with broad implications in pathology.

    ROLE OF CYTOKINES AND OTHER PROPHETIC VARIABLES IN THE DEVELOPMENT AND PROGRESSION OF DISEASE IN PATIENTS SUFFERING FROM COVID-19 MESHD

    Authors: arif malik; Saima Iqbal; Sulayman Waquar; Muhammad Mansoor Hafeez

    doi:10.1101/2020.10.28.20221408 Date: 2020-11-03 Source: medRxiv

    INTRODUCTION: Outbreak of the novel COVID-19 MESHD infection identifies both causative agents that threaten global pandemic in 2003 and 2011. It is an enveloped virus with spike (S) protein PROTEIN attached that facilitates its receptor binding on the surface. Although it has brought about the global interest for the researchers and medical practitioner in the identification of potential targets that may be addressed in order to cope up with the situation. In the current study potential role of cytokines and related inflammatory markers have been identified that interplays in the progression of disease in COVID-19 MESHD patients. MATERIALS AND METHODS: Current study substitutes hundred and fifty (n=150) patients with novel- COVID-19 MESHD and hundred (n=100) healthy controls. After getting informed consent serum samples of the participants were collected and analyzed for their significance in the disease progression. Levels of Interleukins i.e., ( IL-1 HGNC,6,8,10,11) and tumor MESHD tumor HGNC necrosis MESHD factor-alpha ( TNF HGNC-) were determined with help of their specific spectrophotometric and ELISA methods. RESULTS: Findings of study show significant increase in the levels of interleukins and TNF HGNC- that signifies the presence of cytokine storm in worsening the condition in respect to the exposure of COVID-19 MESHD. Levels of IL-1 and 6 were significantly higher in patients (98.69 pg/ml and 71.95 pg/ml) as compared to controls (30.06 pg/ml and 9.46 pg/ml) where, (p=0.001 and 0.007). It also suggests that IL-6 HGNC is most sensitive test with about (98%) sensitivity in comparison with 96%,95%, 95%,93% and 92% in case of IL-10,1,8,11 and TNF-a HGNC respectively. CONCLUSION: Current study elucidate the effects of cytokines and respective inflammatory markers in the progression of the COVID-19 MESHD. Findings show that activation of macrophages and neutrophils have significant role in the worsening of the symptoms and progression of the viral infection MESHD. Thus, use of certain blockers in initial stages could serve with potent benefits in coping up the infectious condition.

    COVID-19 MESHD cytokines and the hyperactive immune response: Synergism of TNF-α HGNC and IFN-γ HGNC in triggering inflammation, tissue damage, and death

    Authors: Evan Peter Williams; Lillian Zalduondo; Colleen Beth Jonsson; Alex R Schuurman; Jan Verhoeff; Saskia D van Asten; Hetty J Bontkes; Siebe G Blok; Janwillem Duitman; Harm Jan Bogaard; Leo Heunks; Rene Lutter; Tom van der Poll; Juan J Garcia Vallejo; Qiqi Cao; Fangjin Chen; Yuqing Chen; Xuelian Cheng; Guohong Deng; Wenyu Ding; Yingmei Feng; Rui Gan; Chuang Guo; Shuai He; Chen Jiang; Juanran Liang; Yi-Min Li; Jun Lin; Yun Ling; Haofei Liu; Jianwei Liu; Nianping Liu; Yang Liu; Meng Luo; Qiang Ma; Qibing Song; Wujianan Sun; Gaoxiang Wang; Feng Wang; Ying Wang; Xiaofeng Wen; Qian Wu; Xiaowei Xie; Xinxin Xiong; Xudong Xing; Hao Xu; Chonghai Yin; Dongdong Yu; Kezhuo Yu; Biao Zhang; Tong Zhang; Jincun Zhao; Peidong Zhao; Jianfeng Zhou; Wei Zhou; Sujuan Zhong; Xiaosong Zhong; Shuye Zhang; Lin Zhu; Ping Zhu; Bing Zou; Jiahua Zou; Zengtao Zuo; Fan Bai; Xi Huang; Xiuwu Bian; Penghui Zhou; Qinghua Jiang; Zhiwei Huang; Jin-Xin Bei; Lai Wei; Xindong Liu; Tao Cheng; Xiangpan Li; Fu-Sheng Wang; Hongyang Wang; Bing Su; Kun Qu; Xiaoqun Wang; JieKai Chen; Ronghua Jin; Zemin Zhang

    doi:10.1101/2020.10.29.361048 Date: 2020-10-29 Source: bioRxiv

    The COVID-19 MESHD COVID-19 MESHD 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 MESHD and lung damage MESHD. Cytokine storm is associated with severe inflammation MESHD and organ damage during COVID-19 MESHD. 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 MESHD, we found that the combined production of TNF- and IFN-{gamma} specifically induced inflammatory cell death MESHD, PANoptosis, characterized by gasdermin-mediated pyroptosis, caspase-8 HGNC-mediated apoptosis, and MLKL HGNC-mediated necroptosis. Deletion of pyroptosis, apoptosis, or necroptosis mediators individually was not sufficient to protect against cell death. However, cells deficient in both RIPK3 HGNC and caspase-8 HGNC or RIPK3 HGNC and FADD HGNC were resistant to this cell death. Mechanistically, the STAT1 HGNC/ IRF1 HGNC axis activated by TNF- and IFN-{gamma} 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- and IFN-{gamma}-induced lethal cytokine shock MESHD that mirrors the pathological symptoms of COVID-19 MESHD. In vivo neutralization of both TNF- and IFN-{gamma} in multiple disease models associated with cytokine storm showed that this treatment provided substantial protection against not only SARS-CoV-2 infection MESHD, but also sepsis MESHD, hemophagocytic lymphohistiocytosis MESHD, and cytokine shock models, demonstrating the broad physiological relevance of this mechanism. Collectively, our findings reveal that blocking the COVID-19 MESHD cytokine-mediated inflammatory cell death MESHD signaling pathway identified in this study may benefit patients with COVID-19 MESHD or other cytokine storm-driven syndromes by limiting inflammation MESHD 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 MESHD and cancers MESHD where TNF- and IFN-{gamma} synergism play key pathological roles.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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