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1.
Biochem J ; 479(5): 609-628, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1730329

ABSTRACT

Two years after the emergence of SARS-CoV-2, our understanding of COVID-19 disease pathogenesis is still incomplete. Despite unprecedented global collaborative scientific efforts and rapid vaccine development, an uneven vaccine roll-out and the emergence of novel variants of concern such as omicron underscore the critical importance of identifying the mechanisms that contribute to this disease. Overt inflammation and cell death have been proposed to be central drivers of severe pathology in COVID-19 patients and their pathways and molecular components therefore present promising targets for host-directed therapeutics. In our review, we summarize the current knowledge on the role and impact of diverse programmed cell death (PCD) pathways on COVID-19 disease. We dissect the complex connection of cell death and inflammatory signaling at the cellular and molecular level and identify a number of critical questions that remain to be addressed. We provide rationale for targeting of cell death as potential COVID-19 treatment and provide an overview of current therapeutics that could potentially enter clinical trials in the near future.


Subject(s)
COVID-19/etiology , COVID-19/pathology , Antiviral Agents , Apoptosis/drug effects , Apoptosis/physiology , COVID-19/drug therapy , Humans , Inflammasomes/physiology , Interferons/metabolism , Necroptosis/physiology , Neutrophils/pathology , Neutrophils/virology , Pyroptosis/physiology , SARS-CoV-2/pathogenicity
2.
Front Immunol ; 12: 700152, 2021.
Article in English | MEDLINE | ID: covidwho-1359189

ABSTRACT

Background: Mucosal-associated invariant T (MAIT) cells are considered to participate of the host immune response against acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, single-cell transcriptomic profiling of MAIT cells in patients with COVID-19 remains unexplored. Methods: We performed single-cell RNA sequencing analyses on peripheral MAIT cells from 13 patients with COVID-19 and 5 healthy donors. The transcriptional profiles of MAIT cells, together with assembled T-cell receptor sequences, were analyzed. Flow cytometry analysis was also performed to investigate the properties of MAIT cells. Results: We identified that differentially expressed genes (DEGs) of MAIT cells were involved in myeloid leukocyte activation and lymphocyte activation in patients with COVID-19. In addition, in MAIT cells from severe cases, more DEGs were enriched in adaptive cellular and humoral immune responses compared with those in moderate cases. Further analysis indicated that the increase of cell cytotoxicity (killing), chemotaxis, and apoptosis levels in MAIT cells were consistent with disease severity and displayed the highest levels in patients with severe disease. Interestingly, flow cytometry analysis showed that the frequencies of pyroptotic MAIT cells, but not the frequencies of apoptotic MAIT cells, were increased significantly in patients with COVID-19, suggesting pyroptosis is one of leading causes of MAIT cell deaths during SARS-CoV-2 infection. Importantly, there were more clonal expansions of MAIT cells in severe cases than in moderate cases. Conclusions: The results of the present study suggest that MAIT cells are likely to be involved in the host immune response against SARS-CoV-2 infection. Simultaneously, the transcriptomic data from MAIT cells provides a deeper understanding of the immune pathogenesis of the disease.


Subject(s)
COVID-19/immunology , Mucosal-Associated Invariant T Cells/immunology , SARS-CoV-2/immunology , Transcriptome/genetics , Base Sequence , COVID-19/pathology , Gene Expression Profiling , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Humans , Lymphocyte Activation/genetics , Pyroptosis/physiology , Sequence Analysis, RNA , Severity of Illness Index , VDJ Exons/genetics
3.
EMBO J ; 40(18): e108249, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1323479

ABSTRACT

SARS-CoV-2 is an emerging coronavirus that causes dysfunctions in multiple human cells and tissues. Studies have looked at the entry of SARS-CoV-2 into host cells mediated by the viral spike protein and human receptor ACE2. However, less is known about the cellular immune responses triggered by SARS-CoV-2 viral proteins. Here, we show that the nucleocapsid of SARS-CoV-2 inhibits host pyroptosis by blocking Gasdermin D (GSDMD) cleavage. SARS-CoV-2-infected monocytes show enhanced cellular interleukin-1ß (IL-1ß) expression, but reduced IL-1ß secretion. While SARS-CoV-2 infection promotes activation of the NLRP3 inflammasome and caspase-1, GSDMD cleavage and pyroptosis are inhibited in infected human monocytes. SARS-CoV-2 nucleocapsid protein associates with GSDMD in cells and inhibits GSDMD cleavage in vitro and in vivo. The nucleocapsid binds the GSDMD linker region and hinders GSDMD processing by caspase-1. These insights into how SARS-CoV-2 antagonizes cellular inflammatory responses may open new avenues for treating COVID-19 in the future.


Subject(s)
COVID-19/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Nucleocapsid/metabolism , Phosphate-Binding Proteins/metabolism , Pyroptosis/physiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Caspase 1/immunology , Caspase 1/metabolism , HEK293 Cells , Host-Pathogen Interactions , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Intracellular Signaling Peptides and Proteins/immunology , Mice , Monocytes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phosphate-Binding Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , THP-1 Cells
4.
Inflammopharmacology ; 29(4): 1049-1059, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1303332

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enter the central nervous system and cause several neurological manifestations. Data from cerebrospinal fluid analyses and postmortem samples have been shown that SARS-CoV-2 has neuroinvasive properties. Therefore, ongoing studies have focused on mechanisms involved in neurotropism and neural injuries of SARS-CoV-2. The inflammasome is a part of the innate immune system that is responsible for the secretion and activation of several pro-inflammatory cytokines, such as interleukin-1ß, interleukin-6, and interleukin-18. Since cytokine storm has been known as a major mechanism followed by SARS-CoV-2, inflammasome may trigger an inflammatory form of lytic programmed cell death (pyroptosis) following SARS-CoV-2 infection and contribute to associated neurological complications. We reviewed and discussed the possible role of inflammasome and its consequence pyroptosis following coronavirus infections as potential mechanisms of neurotropism by SARS-CoV-2. Further studies, particularly postmortem analysis of brain samples obtained from COVID-19 patients, can shed light on the possible role of the inflammasome in neurotropism of SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Central Nervous System/metabolism , Inflammasomes/metabolism , Pyroptosis/physiology , SARS-CoV-2/metabolism , Brain/immunology , Brain/metabolism , COVID-19/immunology , Central Nervous System/immunology , Humans , Inflammasomes/immunology , SARS-CoV-2/immunology
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