The Immunopathogenesis of a Cytokine Storm: The Key Mechanisms Underlying Severe COVID-19

Cytokine & Growth Factor Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

A cytokine storm is marked by excessive pro-inflammatory release, and has emerged as a key factor in severe COVID-19 cases - making it critical therapeutic target. However, its pathophysiology was poorly understood, which hindered effective treatment. SARS-CoV-2 initially disrupts angiotensin signalling, promoting inflammation through ACE-2 downregulation. Some patients' immune systems then fail to shift from innate adaptive immunity, suppressing interferon responses leading pyroptosis neutrophil activation. This amplifies tissue damage inflammation, creating loop. The result the disruption of Th1/Th2 Th17/Treg balances, lymphocyte exhaustion, extensive blood clotting. Cytokine treatments include glucocorticoids suppress system, monoclonal antibodies neutralize specific cytokines, JAK inhibitors block receptor signalling. most treatment options for mitigating infection remain vaccines preventive measure antiviral drugs early stages infection. article synthesizes insights into dysregulation COVID-19, offering framework better understand storms improve monitoring, biomarker discovery, strategies other conditions involving storms.

Language: Английский

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Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 20(7), P. 835 - 849

Published: May 30, 2023

Abstract Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent or unregulated proinflammatory cytokine severe disease outcomes. Previous work suggested that monocyte-derived macrophages (MDMs) resistant unresponsive to SARS-CoV-2 infection. Here, we demonstrate upon phagocytosis of SARS-CoV-2-infected cells, MDMs activated secrete IL-6 TNF. Importantly, in turn mediate activation plasmacytoid dendritic cells (pDCs), leading the secretion high levels IFN-α Furthermore, pDC promoted production by MDMs. This kind was dependent on direct integrin-mediated cell‒cell contacts involved stimulation TLR7 STING signaling pathways. Overall, present study describes a novel potent pathway is linked macrophage-mediated clearance infected cells. These findings suggest infection rate may lead exaggerated responses, which contribute tissue damage disease.

Language: Английский

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Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(9)

Published: April 30, 2024

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation molecular and cellular profiles the full course can link immune programs coordination progression heterogeneity.METHODSWe performed deep immunophenotyping conducted longitudinal multiomics modeling, integrating 10 assays 1,152 Immunophenotyping Assessment in a Cohort (IMPACC) study participants identifying several cascades were significant drivers differential outcomes.RESULTSIncreasing was driven by temporal pattern began early upregulation immunosuppressive metabolites then elevated levels inflammatory cytokines, signatures coagulation, formation neutrophil extracellular traps, T cell functional dysregulation. second cascade, predictive 28-day mortality among critically ill patients, characterized reduced total plasma Igs B cells dysregulated IFN responsiveness. We demonstrated balance disruption between IFN-stimulated genes inhibitors is crucial biomarker mortality, potentially contributing failure viral clearance patients fatal illness.CONCLUSIONOur profiling revealed across omics explain progression, providing insights inform targeted development therapies COVID-19, especially those who are ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, R01AI122220); National Science Foundation (DMS2310836).

Language: Английский

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Interferons and interferon-related pathways in heart disease

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: April 11, 2024

Interferons (IFNs) and IFN-related pathways play key roles in the defence against microbial infection. However, these processes may also be activated during pathogenesis of non-infectious diseases, where they contribute to organ injury, or function a compensatory manner. In this review, we explore IFNs heart disease. We consider cardiac effects type I IFN-stimulated genes (ISGs); emerging role cyclic GMP-AMP synthase (cGAS)-stimulator interferon (STING) pathway; seemingly paradoxical II IFN, IFN-γ; varied actions regulatory factor (IRF) family transcription factors. Recombinant small molecule inhibitors mediators IFN receptor signaling are already employed clinic for treatment some autoimmune infections, cancers. There has been renewed interest because their involvement SARS-CoV-2 infection, relatively recent emergence cGAS-STING as pattern recognition receptor-activated pathway. Whether advances will ultimately result improvements care those experiencing disease remains determined.

Language: Английский

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Gut-brain pathogenesis of post-acute COVID-19 neurocognitive symptoms

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Sept. 28, 2023

Approximately one third of non-hospitalized coronavirus disease 2019 (COVID-19) patients report chronic symptoms after recovering from the acute stage severe respiratory syndrome 2 (SARS-CoV-2) infection. Some most persistent and common complaints this post-acute COVID-19 (PACS) are cognitive in nature, described subjectively as “brain fog” also objectively measured deficits executive function, working memory, attention, processing speed. The mechanisms these sequelae currently not understood. SARS-CoV-2 inflicts damage to cerebral blood vessels intestinal wall by binding angiotensin-converting enzyme (ACE2) receptors evoking production high levels systemic cytokines, compromising brain’s neurovascular unit, degrading barrier, potentially increasing permeability both harmful substances. Such substances hypothesized be produced gut pathogenic microbiota that, given profound effects has on gastrointestinal system, may fourish a result post-COVID-19 dysbiosis. therefore create scenario which neurotoxic neuroinflammatory readily proliferate lumen encounter weakened gaining access brain subsequently producing deficits. Here, we review proposed PACS pathogenesis along gut-brain axis, while identifying specific methodologies that available experimentally measure each individual component model.

Language: Английский

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Time-dependent recruitment of GAF, ISGF3 and IRF1 complexes shapes IFNα and IFNγ-activated transcriptional responses and explains mechanistic and functional overlap

Cellular and Molecular Life Sciences, Journal Year: 2023, Volume and Issue: 80(7)

Published: June 22, 2023

To understand in detail the transcriptional and functional overlap of IFN-I- IFN-II-activated responses, we used an integrative RNAseq-ChIPseq approach Huh7.5 cells characterized genome-wide role pSTAT1, pSTAT2, IRF9 IRF1 time-dependent ISG expression. For first time, our results provide detailed insight timely steps IFNα- IFNγ-induced transcription, which pSTAT1- pSTAT2-containing ISGF3 GAF-like complexes are recruited to individual or combined ISRE GAS composite sites a phosphorylation- manner. Interestingly, genes displayed more heterogeneous expression pattern, as compared (early) (late), with time- phosphorylation-dependent recruitment GAF, after IFNα stimulation GAF IFNγ. Moreover, shared features through transcription factor co-binding closely located sites, were able sustain IFN responsiveness STAT1-, STAT2-, IRF9-, IRF1- IRF9/IRF1-mutant Wt cells. Thus, + site acted molecular switch, depending on available components complexes. Consequently, STAT1, STAT2 identified that part positive feedback loop controlling long-term IFNγ responses. More important, absence any one components, regulation appeared be preserved. Together, these findings further existence novel composite-dependent intracellular amplifier circuit prolonging cellular different types IFNs subsequent antiviral activity. It also offers explanation for existing between

Language: Английский

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Navigating the Post-COVID-19 Immunological Era: Understanding Long COVID-19 and Immune Response

Life, Journal Year: 2023, Volume and Issue: 13(11), P. 2121 - 2121

Published: Oct. 26, 2023

The COVID-19 pandemic has affected the world unprecedentedly, with both positive and negative impacts. significantly impacted immune system, understanding immunological consequences of is essential for developing effective treatment strategies. purpose this review to comprehensively explore provide insights into aspects long COVID-19, a phenomenon where individuals continue experience range symptoms complications, even after acute phase infection subsided. system responds initial by producing various cells molecules, including antibodies, T cells, cytokines. However, in some patients, response becomes dysregulated, leading chronic inflammation persistent symptoms. Long encompasses diverse affecting multiple organ systems, respiratory, cardiovascular, neurological, gastrointestinal systems. In post-COVID-19 era, its impact on have become significant concern. Post-COVID-19 pathology, autoimmunity immune-mediated disorders, also been reported patients. This provides an overview current relationship responses, pathology patient outcomes. Additionally, addresses potential treatments immunomodulatory therapies, rehabilitation programs, mental health support, all which aim improve quality life COVID-19. Understanding complex interplay between crucial targeted therapeutic strategies providing optimal care era.

Language: Английский

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SARS-CoV-2: A Glance at the Innate Immune Response Elicited by Infection and Vaccination

Antibodies, Journal Year: 2024, Volume and Issue: 13(1), P. 13 - 13

Published: Feb. 8, 2024

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to almost seven million deaths worldwide. SARS-CoV-2 causes infection through respiratory transmission and can occur either without any symptoms or with clinical manifestations which be mild, severe or, in some cases, even fatal. Innate immunity provides the initial defense against virus sensing pathogen-associated molecular patterns triggering signaling pathways that activate antiviral inflammatory responses, limit viral replication help identification removal of infected cells. However, temporally dysregulated excessive activation innate immune response is deleterious for host associates COVID-19. In addition its defensive role, pivotal priming adaptive polarizing effector function. This capacity relevant context both natural vaccination. Here, we provide an overview current knowledge responses

Language: Английский

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The potential mechanism of Isodon suzhouensisagainst COVID-19 via EGFR/TLR4 pathways

Deleted Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 26, 2024

Corona Virus Disease 2019 (COVID-19) has brought the new challenges to scientific research. Isodon suzhouensis good anti-inflammatory and antioxidant stress effects, which is considered as a potential treatment for COVID-19. The possibility of COVID-19 with suzhouensis and its mechanism action were explored by employing molecular docking network pharmacology. Network pharmacology used screen drug targets, Lipopolysaccharide (LPS) induced RAW264.7 NR8383 cells inflammation model was experimental verification. Collectively total 209 possible linkages against 18 chemical components from suzhouensis 1194 related targets selected. Among these, 164 common obtained intersection GO KEGG enriched 582 function 87 target proteins pathways, respectively. results studies revealed that rutin, vitexin, isoquercitrin quercetin had significant binding ability SARS-CoV-23CLpro ACE2. In vitro showed extract (ISE) may inhibit activation PI3K/Akt pathway expression level downstream pro-inflammatory factors inhibiting EGFR in LPS. addition, ISE able TLR4/NF-κB signaling exposed Overall, conclude active have strong therapeutic through multi-target, multi-pathway dimensions can be promising candidate

Language: Английский

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Intranasal or airborne transmission-mediated delivery of an attenuated SARS-CoV-2 protects Syrian hamsters against new variants

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 9, 2023

Detection of secretory antibodies in the airway is highly desirable when evaluating mucosal protection by vaccines against a respiratory virus, such as severe acute syndrome coronavirus 2 (SARS-CoV-2). We show that intranasal delivery an attenuated SARS-CoV-2 (Nsp1-K164A/H165A) induces both and systemic IgA IgG male Syrian hamsters. Interestingly, either direct immunization or airborne transmission-mediated Nsp1-K164A/H165A hamsters offers heterologous challenge with variants concern (VOCs) including Delta, Omicron BA.1, BA.2.12.1 BA.5. Vaccinated animals significant reduction tissue viral loads lung inflammation. Similarly viruses bearing BA.1 BA.5 spike boost variant-specific neutralizing mice were first vaccinated modified vaccinia virus Ankara vectors (MVA) expressing full-length WA1/2020 Spike protein. Together, these results demonstrate our may be promising nasal vaccine candidate for boosting immunity future VOCs.

Language: Английский

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