SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein

Molecular Psychiatry, Год журнала: 2022, Номер 28(7), С. 2878 - 2893

Опубликована: Ноя. 1, 2022

Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases probable Parkinson's disease. As microglial NLRP3 inflammasome activation major driver neurodegeneration, here we interrogated whether promote activation. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as COVID-19 pre-clinical model, established the presence virus in brain together with and upregulation comparison to uninfected mice. Next, utilising model monocyte-derived microglia, identified isolates bind enter microglia absence viral replication. This interaction directly induced robust activation, even another priming signal. Mechanistically, demonstrated purified spike glycoprotein activated LPS-primed ACE2-dependent manner. Spike protein could prime through NF-κB signalling, allowing for either ATP, nigericin or α-synuclein. Notably, protein-mediated was significantly enhanced α-synuclein fibrils entirely ablated by NLRP3-inhibition. Finally, demonstrate infected hACE2 treated orally post-infection inhibitory drug MCC950, have reduced increased survival untreated These results support possible mechanism innate immune SARS-CoV-2, which explain vulnerability developing symptoms akin disease individuals, potential therapeutic avenue intervention.

Язык: Английский

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Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice

Nature Aging, Год журнала: 2023, Номер 3(2), С. 202 - 212

Опубликована: Янв. 9, 2023

Язык: Английский

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Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 23(1), С. 43 - 66

Опубликована: Ноя. 29, 2023

Язык: Английский

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Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications

EBioMedicine, Год журнала: 2022, Номер 85, С. 104299 - 104299

Опубликована: Окт. 6, 2022

Язык: Английский

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Small molecules in the treatment of COVID-19

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Дек. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Язык: Английский

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Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Journal of Translational Medicine, Год журнала: 2022, Номер 20(1)

Опубликована: Ноя. 22, 2022

Abstract The innate immune system serves as the first line of defense against invading pathogens; however, dysregulated responses can induce aberrant inflammation that is detrimental to host. Therefore, careful regulation critical during infections. coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2) and has resulted in global morbidity mortality well socio-economic stresses. Innate sensing SARS-CoV-2 multiple host cell pattern recognition receptors leads production various pro-inflammatory cytokines induction inflammatory death. These processes contribute cytokine storm, tissue damage, distress syndrome. Here, we discuss activation contribution this signaling development severity COVID-19. In addition, provide a conceptual framework for immunity driving storm organ damage patients with A better understanding molecular mechanisms regulated needed targeted modalities improve patient outcomes mitigating disease.

Язык: Английский

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Hyperinflammatory Response in COVID-19: A Systematic Review

Viruses, Год журнала: 2023, Номер 15(2), С. 553 - 553

Опубликована: Фев. 16, 2023

COVID-19 is a multisystemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The immunopathogenic conditions of hyperinflammatory response that cause systemic inflammation are extremely linked to its severity. This research sought review immunopathological elements contribute progression. systematic using PUBMED, LILACS, MEDLINE, and SCIELO databases articles between May 2020 July 2022 with following search terms in conjunction “AND”: “SARS-CoV-2”; “COVID-19”; “ARDS” “Cytokine Storm”. quality appraisal risk bias were assessed JBI checklists Cochrane Collaboration’s RoB 2.0 ROBINS-I tools, respectively, for vitro studies pre-defined standard literature. resulted 39 articles. main actors this denote SARS-CoV-2 Spike proteins, cellular proteases, leukocytes, cytokines, proteolytic cascades. “cytokine storm” itself brings several complications host through cytokines such as IL-6 chemokines (such CCL2), which influence tissue apoptosis pyroptosis. causes unfavorable outcomes patients, largely dysregulation immune should be controlled their recovery.

Язык: Английский

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Cell deaths: Involvement in the pathogenesis and intervention therapy of COVID-19

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июнь 13, 2022

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) infection has dramatically influenced various aspects the world. It is urgent to thoroughly study pathology and underlying mechanisms for developing effective strategies prevent treat this threatening disease. universally acknowledged that cell death autophagy are essential crucial maintaining host homeostasis participating in pathogenesis. At present, more than twenty different types have been discovered, some parts which fully understood, whereas need investigation. Increasing studies indicated might play an important role virus pathogenicity. However, knowledge interactions related SARS-CoV-2 between lacks systematic elucidation. Therefore, review, we comprehensively delineate how manipulates diverse (including apoptosis, necroptosis, pyroptosis, ferroptosis, NETosis) itself benefits, simultaneously involved occurrence progression COVID-19, aiming provide a reasonable basis existing interventions further development novel therapies.

Язык: Английский

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The Potential Role of Growth Differentiation Factor 15 in COVID-19: A Corollary Subjective Effect or Not?

Diagnostics, Год журнала: 2022, Номер 12(9), С. 2051 - 2051

Опубликована: Авг. 24, 2022

Coronavirus disease 2019 (COVID-19) is primarily caused by various forms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) variants. COVID-19 characterized hyperinflammation, oxidative stress, multi-organ injury (MOI)-like lung (ALI) and distress (ARDS). Different biomarkers are used in the assessment severity including D-dimer, ferritin, lactate dehydrogenase (LDH), hypoxia-inducible factor (HIF). Interestingly, growth differentiation 15 (GDF15) has recently become a potential biomarker correlated with severity. Thus, this critical review aimed to determine association between GDF15 COVID-19. The perfect function remains not well-recognized; nevertheless, it plays vital role controlling cell growth, apoptosis inflammatory activation. Furthermore, may act as anti-inflammatory pro-inflammatory signaling diverse cardiovascular complications. release activated factors cytokines macrophage colony-stimulating (M-CSF), angiotensin II (AngII) p53. Therefore, higher expression might compensatory mechanism stabilize counteract dysregulated reactions. In conclusion, an cytokine that could be associated Increased against hyperinflammation exaggerated immune response Experimental, preclinical large-scale clinical studies warranted regard.

Язык: Английский

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The role of cell death in SARS-CoV-2 infection

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 20, 2023

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), showing high infectiousness, resulted in an ongoing pandemic termed disease 2019 (COVID-19). COVID-19 cases often experience distress syndrome, which has caused millions of deaths. Apart from triggering inflammatory and immune responses, many viral infections can cause programmed cell death infected cells. Cell mechanisms have a vital role maintaining suitable environment to achieve normal functionality. Nonetheless, these processes are dysregulated, potentially contributing pathogenesis. Over the past decades, multiple pathways becoming better understood. Growing evidence suggests that induction by may significantly contributes infection pathogenicity. However, interaction SARS-CoV-2 with death, together its associated mechanisms, is yet be elucidated. In this review, we summarize existing concerning molecular modulation as well viral-host interactions, shed new light on antiviral therapy against SARS-CoV-2.

Язык: Английский

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