SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112189 - 112189

Published: Feb. 17, 2023

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or fragments released from cells during infection, reaching different tissues, including the CNS, irrespective of presence viral RNA. Here, we demonstrate brain infusion mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show neuroinflammation and hippocampal microgliosis mediate Spike-induced memory via complement-dependent engulfment synapses. Genetic pharmacological blockage Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination induced by infusion. Accordingly, cohort 86 who recovered mild COVID-19, genotype GG TLR4-2604G>A (rs10759931) associated poor outcome. These results identify TLR4 as key target to investigate long-term after COVID-19 infection humans rodents.

Language: Английский

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The role of inflammasomes in human diseases and their potential as therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 5, 2024

Abstract Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three components: an upstream sensor molecule is connected to downstream effector such as caspase-1 through adapter ASC. Inflammasome formation typically occurs response infectious agents or cellular damage. The active then triggers activation, followed by secretion of pro-inflammatory cytokines pyroptotic cell death. Aberrant activation activity contribute development diabetes, cancer, several cardiovascular neurodegenerative disorders. As result, recent research increasingly focused on investigating mechanisms regulate assembly well potential targeting inflammasomes treat various diseases. Multiple clinical trials currently underway evaluate therapeutic distinct inflammasome-targeting therapies. Therefore, understanding how different disease pathology may have significant implications for developing novel strategies. In this article, we provide summary biological pathological roles health disease. We also highlight key evidence suggests could be strategy new disease-modifying therapies effective conditions.

Language: Английский

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Possible Pathogenesis and Prevention of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(9), P. 8034 - 8034

Published: April 28, 2023

Patients who have recovered from coronavirus disease 2019 (COVID-19) infection may experience chronic fatigue when exercising, despite no obvious heart or lung abnormalities. The present lack of effective treatments makes managing long COVID a major challenge. One the underlying mechanisms be mitochondrial dysfunction. Severe acute respiratory syndrome 2 (SARS-CoV-2) infections can alter mitochondria responsible for energy production in cells. This alteration leads to dysfunction which, turn, increases oxidative stress. Ultimately, this results loss integrity and cell death. Moreover, viral proteins bind complexes, disrupting function causing immune cells over-react. over-reaction inflammation potentially symptoms. It is important note that roles damage inflammatory responses caused by SARS-CoV-2 development are still being elucidated. Targeting provide promising new clinical approaches long-COVID patients; however, further studies needed evaluate safety efficacy such approaches.

Language: Английский

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Inflammasomes in neurological disorders — mechanisms and therapeutic potential

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(2), P. 67 - 83

Published: Jan. 9, 2024

Language: Английский

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iPSC‐derived human cortical organoids display profound alterations of cellular homeostasis following SARS‐CoV‐2 infection and Spike protein exposure

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(4)

Published: Feb. 14, 2025

Abstract COVID‐19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting detrimental impact SARS‐CoV‐2 or the viral Spike protein on central nervous system. Nonetheless, molecular pathway behind pathology and presumed neurotropism remains largely unexplored. We generated human cortical organoids (HCOs) derived from induced pluripotent stem cells (hiPSC) assess: (1) expression main entry factors; (2) their vulnerability infection; (3) infection exposure transcriptome. Results proved that HCOs express receptors co‐receptors; may be productively infected by SARS‐CoV‐2; particles released SARS‐CoV‐2‐infected are able re‐infect another cellular line; (4) resulted in activation apoptotic stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when exposed alone. The data obtained demonstrate likely infects probably through binding ACE2, CD147, NRP1 factors. Furthermore, alone sufficient disrupt homeostasis induce neurotoxic effects, potentially contributing onset long‐COVID symptoms.

Language: Английский

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NLRP3 inflammasome in neurodegenerative disease

Translational research, Journal Year: 2022, Volume and Issue: 252, P. 21 - 33

Published: Aug. 9, 2022

Language: Английский

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Risk of Thrombosis during and after a SARS-CoV-2 Infection: Pathogenesis, Diagnostic Approach, and Management

Hematology Reports, Journal Year: 2023, Volume and Issue: 15(2), P. 225 - 243

Published: April 3, 2023

Coronavirus disease 2019 (COVID-19) increases the risk of thromboembolic events, especially in patients with severe infections requiring intensive care and cardiorespiratory support. COVID-19 complications have a higher death, if they survive, these are expected to negatively affect patients’ quality life. Moreover, recent data reported that thromboembolism remains high months after infection. Therefore, understanding pathogenesis thrombosis setting may facilitate early prevention treatment COVID-19-associated reduce concomitant morbidity, mortality, disability. This review will first discuss clinical characteristics infections, particularly regard underlying pathophysiology. Then, at molecular cellular levels be comprehensively reviewed. Next, manifestations venous arterial as well potential benefits several laboratory markers further discussed. Lastly, preventive therapeutic management during also explained.

Language: Английский

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SARS-COV-2 viroporins activate the NLRP3-inflammasome by the mitochondrial permeability transition pore

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 20, 2023

Background Compared to healthy controls, severe COVID19 patients display increased levels of activated NLRP3-inflammasome (NLRP3-I) and interleukin (IL)-1β. SARS-CoV-2 encodes viroporin proteins E Orf3a(2-E+2-3a) with homologs SARS-CoV-1, 1-E+1-3a, which elevate NLRP3-I activation; by an unknown mechanism. Thus, we investigated how 2-E+2-3a activates the better understand pathophysiology COVID-19. Methods We generated a polycistronic expression-vector co-expressing from single transcript. To elucidate NLRP3-I, reconstituted in 293T cells used THP1-derived macrophages monitor secretion mature IL-1β. Mitochondrial physiology was assessed using fluorescent microscopy plate reader assays, release mitochondrial DNA (mtDNA) detected cytosolic-enriched fractions Real-Time PCR. Results Expression cytosolic Ca++ elevated Ca++, taken up through MCUi11-sensitive calcium uniporter. Increased stimulated NADH, reactive oxygen species (mROS) production mtDNA into cytosol. displayed Increasing antioxidant defenses via treatment MnTBAP or genetic expression mCAT abolished elevation mROS, levels, NLRP3-activated-IL-1β. The 2-E+2-3a-induced NLRP3-activated-IL-1β were absent lacking blocked treated mitochondrial-permeability-pore(mtPTP)-specific inhibitor NIM811. Conclusion Our findings revealed that mROS NIM811-sensitive mitochondrial-permeability-pore(mtPTP), activating inflammasome. Hence, interventions targeting mtPTP may mitigate severity COVID-19 cytokine storms.

Language: Английский

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NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis

Cardiovascular Research, Journal Year: 2023, Volume and Issue: 119(11), P. 2046 - 2060

Published: May 30, 2023

Abstract Immunothrombosis—immune-mediated activation of coagulation—is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines the interleukin (IL)-1 family, IL-1β IL-18, induces pyroptotic cell death. Activation NLRP3 pathway also promotes immunothrombotic programs including release neutrophil extracellular traps tissue factor by leukocytes, prothrombotic responses platelets vascular endothelium. occurs patients with COVID-19 pneumonia. In preclinical models, blockade restrains COVID-19-like hyperinflammation pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety efficacy is approved for treatment hypoxaemic early signs hyperinflammation. non-selective inhibitor colchicine reduced hospitalization death a subgroup outpatients not COVID-19. Additional trials testing blockers are inconclusive or ongoing. We herein outline contribution to COVID-19-associated coagulopathy, review clinical evidence suggesting an engagement pathogenesis summarize current efforts target COVID-19, discuss challenges, unmet gaps, therapeutic potential that inflammasome-targeted strategies may provide inflammation-driven thrombotic disorders

Language: Английский

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SARS-CoV-2 Related Antibody-Dependent Enhancement Phenomena In Vitro and In Vivo

Microorganisms, Journal Year: 2023, Volume and Issue: 11(4), P. 1015 - 1015

Published: April 13, 2023

Antibody-dependent enhancement (ADE) is a phenomenon in which antibodies produced the body after infection or vaccination may enhance subsequent viral infections vitro and vivo. Although rare, symptoms of diseases are also enhanced by ADE following This thought to be due production with low neutralizing activity that bind virus facilitate entry, antigen-antibody complexes cause airway inflammation, predominance T-helper 2 cells among immune system leads excessive eosinophilic tissue infiltration. Notably, disease different phenomena overlap. In this article, we will describe three types ADE: (1) Fc receptor (FcR)-dependent macrophages, (2) FcR-independent other cells, (3) FcR-dependent cytokine macrophages. We their relationship natural infection, discuss possible involvement COVID-19 pathogenesis.

Language: Английский

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