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1.
Int Immunopharmacol ; 104: 108516, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1611782

ABSTRACT

Coronavirus disease 2019 (Covid-19) is a worldwide infectious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). In severe SARS-CoV-2 infection, there is severe inflammatory reactions due to neutrophil recruitments and infiltration in the different organs with the formation of neutrophil extracellular traps (NETs), which involved various complications of SARS-CoV-2 infection. Therefore, the objective of the present review was to explore the potential role of NETs in the pathogenesis of SARS-CoV-2 infection and to identify the targeting drugs against NETs in Covid-19 patients. Different enzyme types are involved in the formation of NETs, such as neutrophil elastase (NE), which degrades nuclear protein and release histones, peptidyl arginine deiminase type 4 (PADA4), which releases chromosomal DNA and gasdermin D, which creates pores in the NTs cell membrane that facilitating expulsion of NT contents. Despite of the beneficial effects of NETs in controlling of invading pathogens, sustained formations of NETs during respiratory viral infections are associated with collateral tissue injury. Excessive development of NETs in SARS-CoV-2 infection is linked with the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due to creation of the NETs-IL-1ß loop. Also, aberrant NTs activation alone or through NETs formation may augment SARS-CoV-2-induced cytokine storm (CS) and macrophage activation syndrome (MAS) in patients with severe Covid-19. Furthermore, NETs formation in SARS-CoV-2 infection is associated with immuno-thrombosis and the development of ALI/ARDS. Therefore, anti-NETs therapy of natural or synthetic sources may mitigate SARS-CoV-2 infection-induced exaggerated immune response, hyperinflammation, immuno-thrombosis, and other complications.


Subject(s)
Acute Lung Injury/immunology , Anti-Inflammatory Agents/pharmacology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Extracellular Traps/immunology , Acute Lung Injury/prevention & control , Acute Lung Injury/virology , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Humans , Immunity, Innate/drug effects , Leukocyte Elastase/antagonists & inhibitors , Leukocyte Elastase/metabolism , Neutrophil Infiltration/drug effects , Phosphate-Binding Proteins/antagonists & inhibitors , Phosphate-Binding Proteins/metabolism , Pore Forming Cytotoxic Proteins/antagonists & inhibitors , Pore Forming Cytotoxic Proteins/metabolism , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Protein-Arginine Deiminase Type 4/metabolism , SARS-CoV-2/immunology
2.
J Mol Biol ; 434(4): 167409, 2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1587212

ABSTRACT

The discovery of pyroptosis and its subsequent implications in infection and immunity has uncovered a new angle of host-defence against pathogen assault. At its most simple, gasdermin-mediated pyroptosis in bacterial infection would be expected to remove pathogens from the relative safety of the cytosol or pathogen containing vacuole/phagosome whilst inducing a rapid and effective immune response. Differences in gasdermin-mediated pyroptosis between cell types, stimulation conditions, pathogen and even animal species, however, make things more complex. The excessive inflammation associated with the pathogen-induced gasdermin-mediated pyroptosis contributes to a downward spiral in sepsis. With no currently approved effective treatment options for sepsis understanding how gasdermin-mediated pyroptotic pathways are regulated provides an opportunity to identify novel therapeutic candidates against this complex disease. In this review we cover recent advances in the field of gasdermin-mediated pyroptosis with a focus on bacterial infection and sepsis models in the context of humans and other animal species. Importantly we also consider why there is considerable redundancy set into these ancient immune pathways.


Subject(s)
Bacterial Infections , Phosphate-Binding Proteins , Pore Forming Cytotoxic Proteins , Pyroptosis , Sepsis , Animals , Bacterial Infections/metabolism , Bacterial Infections/pathology , Humans , Inflammasomes , Phosphate-Binding Proteins/metabolism , Pore Forming Cytotoxic Proteins/metabolism , Sepsis/metabolism , Sepsis/pathology
3.
Nat Rev Immunol ; 21(11): 694-703, 2021 11.
Article in English | MEDLINE | ID: covidwho-1349668

ABSTRACT

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in life-threatening disease in a minority of patients, especially elderly people and those with co-morbidities such as obesity and diabetes. Severe disease is characterized by dysregulated cytokine release, pneumonia and acute lung injury, which can rapidly progress to acute respiratory distress syndrome, disseminated intravascular coagulation, multisystem failure and death. However, a mechanistic understanding of COVID-19 progression remains unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates inflammasomes, which are large multiprotein assemblies that are broadly responsive to pathogen-associated and stress-associated cellular insults, leading to secretion of the pleiotropic IL-1 family cytokines (IL-1ß and IL-18), and pyroptosis, an inflammatory form of cell death. We further discuss potential mechanisms of inflammasome activation and clinical efforts currently under way to suppress inflammation to prevent or ameliorate severe COVID-19.


Subject(s)
COVID-19/immunology , Inflammasomes/immunology , Animals , COVID-19/pathology , COVID-19/physiopathology , Cytokines/immunology , Humans , Inflammasomes/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Phosphate-Binding Proteins/metabolism , Pyroptosis , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , Severity of Illness Index
4.
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
5.
Mol Med Rep ; 24(2)2021 Aug.
Article in English | MEDLINE | ID: covidwho-1271003

ABSTRACT

Coronavirus disease 2019 (COVID­19), caused by the severe acute respiratory syndrome coronavirus­2 (SARS­CoV­2), led to an outbreak of viral pneumonia in December 2019. The present study aimed to investigate the host inflammatory response signature­caused by SARS­CoV­2 in human corneal epithelial cells (HCECs). The expression level of angiotensin­converting enzyme 2 (ACE2) in the human cornea was determined via immunofluorescence. In vitro experiments were performed in HCECs stimulated with the SARS­CoV­2 spike protein. Moreover, the expression levels of ACE2, IL­8, TNF­α, IL­6, gasdermin D (GSDMD) and IL­1ß in HCECs were detected using reverse transcription­quantitative PCR and/or western blotting. It was identified that ACE2 was expressed in normal human corneal epithelium and HCECs cultured in vitro. Furthermore, the expression levels of IL­8, TNF­α and IL­6 in HCECs were decreased following SARS­CoV­2 spike protein stimulation, while the expression levels of GSDMD and IL­1ß were increased. In conclusion, the present results demonstrated that the SARS­CoV­2 spike protein suppressed the host inflammatory response and induced pyroptosis in HCECs. Therefore, blocking the ACE2 receptor in HCECs may reduce the infection rate of COVID­19.


Subject(s)
Epithelium, Corneal/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Cells, Cultured , Cornea/cytology , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial Cells/virology , Epithelium, Corneal/virology , Female , Humans , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Male , Middle Aged , Phosphate-Binding Proteins/genetics , Phosphate-Binding Proteins/metabolism , Pyroptosis , Spike Glycoprotein, Coronavirus/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation
6.
J Biol Chem ; 295(41): 14040-14052, 2020 10 09.
Article in English | MEDLINE | ID: covidwho-704089

ABSTRACT

Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8- and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.


Subject(s)
Caspase 8/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Animals , Cells, Cultured , Coronavirus/physiology , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/veterinary , Cytokines/metabolism , Inflammasomes/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Macrophages/cytology , Macrophages/metabolism , Macrophages/virology , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Necroptosis , Phosphate-Binding Proteins/genetics , Phosphate-Binding Proteins/metabolism
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