Gasdermin-D activation by SARS-CoV-2 trigger NET and mediate COVID-19 immunopathology

Silva, Camila M.S.; Wanderley, Carlos W.; Veras, Flávio P.; Goncalves, Augusto Veloso; Lima, Mikhael Haruo Fernandes de; Toller-Kawahisa, Juliana E; Gomes, Giovanni Freitas; Nascimento, Daniele C.; Monteiro, Valter V S; Paiva, Isadora Marques; Almeida, Cicero J. L. R.; Caetité, Diego B; Silva, Juliana Costa; Lopes, M. Beatriz S.; Bonjorno, Letícia Pastorelli; Giannini, Marcela C; Amaral, Natália Brasil; Benatti, Maíra Nilson; Damasceno, Luis Eduardo Alves; Silva, Bruna Manuella Souza; Schneider, Ayda Henriques; Castro, Ícaro Maia Santos de; Silva, Juan Carlo Santos; Vasconcelos, Amanda Pereira; Gonçalves, Tiago Tomazini; Batah, Sabrina Setembre; Rodrigues, Tamara Silva; Costa, Victor Ferreira; Pontelli, Marjorie Cornejo; Martins, Ronaldo B.; Martins, Timna Varela; Espósito, Danillo Lucas Alves; Cebinelli, Guilherme S; Fonseca, Benedito Antônio Lopes da; Leiria, Luiz O.; Cunha, Larissa D.; Arruda, Eurico; Nakaya, Helder I.; Fabro, Alexandre Todorovic; Oliveira, Renê Donizeti Ribeiro de; Zamboni, Dario S.; Louzada, Paulo; Cunha, Thiago Mattar; Alves‐Filho, José C.; Cunha, Fernando Q.

doi:10.1101/2022.01.24.22269768

Cited by 6 publications

(6 citation statements)

References 44 publications

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“…102 Besides, neutralizing Abs/vaccines accompanied with drugs inhibiting signaling pathways that orchestrate SARS-CoV-2 immunopathology could also improve treatment outcomes. 103 Further, a combination of cocktail mAbs with broad epitopes are reported to retain Omicron neutralization. 48,53,104,105 But, broad epitope recognizing mAbs like sotrovimab are not recommended for hospitalized and intubated COVID-19 patients.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

Immune Evasion by the Highly Mutated SARS-CoV-2 Omicron Variant

Mengist¹,

Kombe²,

Jin³

2022

IDR

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The currently circulating SARS-CoV-2 Omicron variant posed a big challenge for the ongoing pandemic prevention and control activities. The critical concern is whether the current vaccines and therapeutics are capable of fully controlling this variant. Omicron has several mutations mainly concentrated in the receptor-binding domain (RBD) which is the main target for neutralizing antibodies and vaccine-elicited sera, and it is reportedly evading immunity. However, the degree to which the Omicron evades immunity and its impact on the prevention and control activities requires recent and continuous scrutiny. Despite several reports are available, updated and recent discussions are important to tackle the ongoing pandemic especially due to the emerging SARS-CoV-2 variants. Therefore, new insights on designing effective preventive and control measures is utmost important. This review discusses the extent of immune evasion by the Omicron variant and forwards important directions which could have valuable contributions to design alternative strategies in fighting against SARS-Co-2 variants.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

Immune Evasion by the Highly Mutated SARS-CoV-2 Omicron Variant

Mengist¹,

Kombe²,

Jin³

2022

IDR

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“…For instance, high expression of GSDMD has been associated with neutrophil extracellular trap (NET) structures in the lungs of patients with COVID-19. Pharmacological inhibition of GSDMD through treatment with the inhibitor disulfiram reduces NET release and organ damage in a mouse model of SARS-CoV-2 infection, suggesting that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology ( 84 ). These functions require further study.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Core histones are replication-dependent clustered genes, and their expression only occurs during the S phase of the cell cycle [50,51]. Histones are the major component of neutrophil extracellular traps (NETs), which consist of network-like antimicrobial structures bearing nuclear proteins, DNA, and cytotoxic enzymes that capture and kill microorganisms [52,53]. This mechanism is part of the innate immune response and can be triggered by pro-inflammatory cytokines, LPS, intracellular ROS, microorganisms, and chemical agents in a process called NETosis [52].…”

Section: Neutrophil Extracellular Trap Formation (Nets) and Autoimmunitymentioning

confidence: 99%

Transcriptional Profiling of SARS-CoV-2-Infected Calu-3 Cells Reveals Immune-Related Signaling Pathways

Pereira,

da Silva Felipe,

de Freitas

et al. 2023

Pathogens

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The COVID-19 disease, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), emerged in late 2019 and rapidly spread worldwide, becoming a pandemic that infected millions of people and caused significant deaths. COVID-19 continues to be a major threat, and there is a need to deepen our understanding of the virus and its mechanisms of infection. To study the cellular responses to SARS-CoV-2 infection, we performed an RNA sequencing of infected vs. uninfected Calu-3 cells. Total RNA was extracted from infected (0.5 MOI) and control Calu-3 cells and converted to cDNA. Sequencing was performed, and the obtained reads were quality-analyzed and pre-processed. Differential expression was assessed with the EdgeR package, and functional enrichment was performed in EnrichR for Gene Ontology, KEGG pathways, and WikiPathways. A total of 1040 differentially expressed genes were found in infected vs. uninfected Calu-3 cells, of which 695 were up-regulated and 345 were down-regulated. Functional enrichment analyses revealed the predominant up-regulation of genes related to innate immune response, response to virus, inflammation, cell proliferation, and apoptosis. These transcriptional changes following SARS-CoV-2 infection may reflect a cellular response to the infection and help to elucidate COVID-19 pathogenesis, in addition to revealing potential biomarkers and drug targets.

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Gasdermin-D activation by SARS-CoV-2 trigger NET and mediate COVID-19 immunopathology

Cited by 6 publications

References 44 publications

Immune Evasion by the Highly Mutated SARS-CoV-2 Omicron Variant

Immune Evasion by the Highly Mutated SARS-CoV-2 Omicron Variant

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

Transcriptional Profiling of SARS-CoV-2-Infected Calu-3 Cells Reveals Immune-Related Signaling Pathways

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