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      ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection

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          Abstract

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause significant morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. While IFN-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced ZBP1-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with β-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-β treatment following β-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Zα domain suppressed cell death and protected the mice from IFN-mediated lethality during β-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur.

          Abstract

          ZBP1 drives pathology during IFN therapy in coronavirus infection.

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          Most cited references112

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

            In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
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              Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

              Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draft
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Validation
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Validation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: Visualization
                Role: Investigation
                Role: Formal analysisRole: Investigation
                Role: Formal analysisRole: MethodologyRole: Resources
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draft
                Role: ConceptualizationRole: InvestigationRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: Project administrationRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: InvestigationRole: VisualizationRole: Writing - review & editing
                Role: MethodologyRole: ResourcesRole: Writing - original draft
                Role: MethodologyRole: ResourcesRole: Validation
                Role: MethodologyRole: Project administrationRole: Supervision
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing
                Journal
                Sci Immunol
                Sci Immunol
                sciimmunol
                immunology
                Science Immunology
                American Association for the Advancement of Science
                2470-9468
                19 May 2022
                19 May 2022
                : eabo6294
                Affiliations
                [ 1 ]Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
                [ 2 ]UTHSC Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN, USA
                [ 3 ]Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
                [ 4 ]Center for Advanced Genome Engineering (CAGE), St. Jude Children’s Research Hospital, Memphis, TN, USA
                [ 5 ]Institute of Pulmonary Medicine and Sleep Disorders, Continental Hospitals, Asian Institute of Gastroenterology, Hyderabad, India
                [ 6 ]Department of Basic Science, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
                [ 7 ]Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
                [ 8 ]Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
                [ 9 ]Department of Microbiology, Immunology, & Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA
                Author notes
                [# ]

                Equal contribution

                [ * ]Correspondence should be addressed to: Thirumala-Devi Kanneganti, Thirumala-Devi.Kanneganti@ 123456StJude.org
                Author information
                https://orcid.org/0000-0001-6567-5621
                https://orcid.org/0000-0001-7500-782X
                https://orcid.org/0000-0003-1779-3150
                https://orcid.org/0000-0002-6827-5495
                https://orcid.org/0000-0003-3609-833X
                https://orcid.org/0000-0001-8855-9447
                https://orcid.org/0000-0002-9701-5035
                https://orcid.org/0000-0002-0710-9514
                https://orcid.org/0000-0001-9924-2226
                https://orcid.org/0000-0002-5564-1775
                https://orcid.org/0000-0002-3785-0530
                https://orcid.org/0000-0002-7535-0545
                https://orcid.org/0000-0002-3793-585X
                https://orcid.org/0000-0002-4397-7132
                https://orcid.org/0000-0002-2640-7672
                https://orcid.org/0000-0002-6395-6443
                Article
                abo6294
                10.1126/sciimmunol.abo6294
                9161373
                35587515
                e46c38fe-3e30-4b66-bb6a-aa0b74ef8400
                Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 February 2022
                : 16 May 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI101935
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI124346
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI160179
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AR056296
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA253095
                Funded by: FundRef http://dx.doi.org/10.13039/100012524, American Lebanese Syrian Associated Charities;
                Award ID: N/A
                Categories
                Research Articles
                Research Articles
                R-Articles
                Coronavirus
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