Mucosal immune response in biology, disease prevention and treatment

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 7, 2025

Abstract The mucosal immune system, as the most extensive peripheral network, serves frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion establishing tolerance. A comprehensive understanding immunity essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing overall impact on body. Despite its importance, our knowledge remains incomplete, necessitating further research. outbreak severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored critical role disease prevention treatment. This systematic review focuses dynamic interactions between mucosa-associated lymphoid structures related diseases. We delve into basic functions these tissues during processes explore intricate regulatory networks mechanisms involved. Additionally, we summarize novel therapies clinical research advances immunity-related also addresses challenges vaccines, which aim to induce specific responses while maintaining tolerance non-pathogenic microbes. Innovative therapies, such nanoparticle vaccines inhalable antibodies, show promise enhancing offer potential improved

Language: Английский

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Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 6, 2025

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed condensation proteins, nucleic acids, other molecules-in driving efficient dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression intracellular signal transduction, enabling rapid finely tuned responses. Their ability regulate signaling pathways is particularly significant, it requires a careful balance between flexibility precision. Disruption this can lead pathological conditions, including neurodegenerative diseases, cancer, viral infections. Consequently, emerged promising therapeutic targets, with potential offer novel approaches disease treatment. In review, we present recent insights into regulatory mechanisms by which influence pathways, roles health disease, strategies for modulating condensate dynamics approach. Understanding these emerging principles may provide valuable directions developing effective treatments targeting aberrant behavior diseases.

Language: Английский

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The role of SARS-CoV-2-mediated NF-κB activation in COVID-19 patients

Hypertension Research, Journal Year: 2023, Volume and Issue: 47(2), P. 375 - 384

Published: Oct. 23, 2023

Abstract The SARS-CoV-2 pandemic, now in its third year, has had a profound impact on public health and economics all over the world. Different populations showed varied susceptibility to this virus mortality after infection. Clinical laboratory data revealed that uncontrolled inflammatory response plays an important role their poor outcome. Herein, we summarized of NF-κB activation during invasion replication, particularly angiotensin-converting enzyme 2 (ACE2)-mediated activation. Then COVID-19 drugs’ problems. A favorable prognosis is linked with timely treatment inhibitors, such as TNFα, IL-1β, IL-6 monoclonal antibodies. However, further clinical researches are still required clarify time window, dosage administration, contraindication, potential side effects these drugs, for patients hypertension, hyperglycemia, diabetes, or other chronic diseases.

Language: Английский

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Endoplasmic reticulum-associated SARS-CoV-2 ORF3a elicits heightened cytopathic effects despite robust ER-associated degradation

mBio, Journal Year: 2023, Volume and Issue: 15(1)

Published: Dec. 11, 2023

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF3a protein plays a vital role in viral pathogenesis and disease 2019 (COVID-19). Like the spike protein, mutates frequently, certain variants are associated with severity of COVID-19. Given clinical significance functional implications mutations, we conducted comprehensive mutagenesis study targeting various known elements revealed two distinctive types proteins based on their subcellular localizations: primarily localize lysosomal membrane (L-ORF3a) those present endoplasmic reticulum (E-ORF3a). The objective this was to contrast mechanistic distinctions between these proteins. We examined six distinct mutants assessed effects cellular oxidative stress, nuclear factor kappa B-induced cytokine production, cell death. Mechanistically, explored ORF3a-induced ER autophagy, interactions relevant Our findings indicate that induce cytopathic through similar mechanism, irrespective location. However, E-ORF3a elicit more pronounced despite lower abundance minimal impact stress autophagy when compared L-ORF3a This discrepancy is attributed ER-associated degradation since bind ubiquitin E3 ligase TRIM59. Inhibition 26S proteasome partially restores levels response. suggests even small quantity can lead significant due delicate nature ER. underscores intricate interplay dynamic signaling within compartments response ORF3a. IMPORTANCE severe pandemic has tragically claimed millions lives (COVID-19), there remains critical gap our understanding precise molecular mechanisms responsible for fatality. One key interest SARS-CoV-2 which been identified as potent inducer host proinflammatory responses capable triggering catastrophic storm, primary contributor COVID-19-related deaths. Moreover, ORF3a, much like exhibits propensity frequent linked previous research unveiled mutant proteins, categorized by localizations, setting stage comparative investigation into disparities variants. natural promise provide invaluable insights potential roles undertaken

Language: Английский

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A live attenuated SARS-CoV-2 vaccine constructed by dual inactivation of NSP16 and ORF3a

EBioMedicine, Journal Year: 2025, Volume and Issue: 114, P. 105662 - 105662

Published: March 25, 2025

Language: Английский

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Impact of SARS-CoV-2 Wuhan and Omicron Variant Proteins on Type I Interferon Response

Viruses, Journal Year: 2025, Volume and Issue: 17(4), P. 569 - 569

Published: April 15, 2025

SARS-CoV-2 has demonstrated a remarkable capacity for immune evasion. While initial studies focused on the Wuhan variant and adaptive immunity, later emerging strains such as Omicron exhibit mutations that may alter their immune-modulatory properties. We performed comprehensive review of evasion mechanisms associated with viral proteins to focus evolutionary dynamics modulation. systematically analyzed compared impact all currently known type I interferon (IFN) responses using dual-luciferase reporter assay carrying an interferon-inducible promoter. Results revealed Nsp1, Nsp5, Nsp14, ORF6 are potent IFN inhibitors conserved across strains. Notably, we identified strain-specific differences, Nsp6 Spike exhibiting enhanced suppression in Omicron, whereas Envelope protein largely retained this function. To extend these findings, investigated selected primary human endothelial cells also observed differences response higher expressing strain variant, suggesting Omicron’s adaptational contribute damped course pandemic’s trajectory.

Language: Английский

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Acute COVID-19 and LongCOVID syndrome – molecular implications for therapeutic strategies - review

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 17, 2025

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been recognized not only for its acute effects but also ability to cause LongCOVID (LCS), a condition characterized by persistent symptoms affecting multiple organ systems. This review examines the molecular and immunological mechanisms underlying LCS, with particular focus on autophagy inhibition, chronic inflammation, oxidative, nitrosative calcium stress, viral persistence autoimmunology. Potential pathophysiological involved in LCS include (1) autoimmune activation, (2) latent persistence, where SARS-CoV-2 continues influence host metabolism, (3) reactivation of pathogens such as Epstein-Barr virus (EBV) or cytomegalovirus (CMV), exacerbating immune metabolic dysregulation, (4) possible inflammatory body fails restore post-infection homeostasis. The manipulation cellular pathways proteins is critical aspect virus' evade clearance establish long-term dysfunction. Viral NSP13, ORF3a ORF8 have shown disrupt autophagy, thereby impairing promoting evasion. In addition, mitochondrial dysfunction, dysregulated signaling, oxidative HIF-1α activation Nrf2 inhibition create self-sustaining feedback loop that contributes tissue damage symptoms. Therefore understanding basis development effective therapeutic strategies. Targeting glycolysis restoration homeostasis may provide novel strategies mitigate consequences infection. Future research should personalized interventions based dominant perturbations individual patients.

Language: Английский

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SARS-CoV-2 and the DNA damage response

Journal of General Virology, Journal Year: 2023, Volume and Issue: 104(11)

Published: Nov. 10, 2023

The recent coronavirus disease 2019 (COVID-19) pandemic was caused by severe acute respiratory syndrome 2 (SARS-CoV-2). COVID-19 is characterized distress, multiorgan dysfunction and, in some cases, death. virus also responsible for post-COVID-19 condition (commonly referred to as ‘long COVID’). SARS-CoV-2 a single-stranded, positive-sense RNA with genome of approximately 30 kb, which encodes 26 proteins. It has been reported affect multiple pathways infected cells, resulting, many the induction ‘cytokine storm’ and cellular senescence. Perhaps because it an virus, replicating largely cytoplasm, effect SARS-Cov-2 on stability DNA damage responses (DDRs) received relatively little attention. However, now becoming clear that causes DNA, shown presence micronuclei, repair foci increased comet tails cells. This review considers evidence indicating how instability, deregulates cell cycle targets specific components DDR pathways. significance virus’s ability cause senescence considered, are implications instability patients suffering from long COVID.

Language: Английский

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Linear ubiquitination mediates coronavirus NSP14-induced NF-κB activation

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 30, 2024

Human coronaviruses exhibit a spectrum of symptoms, ranging from mild seasonal colds to severe respiratory manifestations. Despite progress in understanding the host's innate defense mechanisms against coronaviruses, how these viruses manipulate immune response promote inflammation remains elusive. In this study, we unveil role coronavirus nonstructural protein 14 (NSP14) leveraging linear ubiquitin chain assembly complex (LUBAC) instigate NF-κB activation, thereby triggering proinflammatory responses. Our findings uncover that HOIL-1-interacting (HOIP) directly engages with NSP14, conferring polyubiquitin chains onto NSP14. Consequently, ubiquitinated NSP14 recruits NEMO and initiates activation IKK complex. This NSP14-induced stimulates expression factors but not type I interferon, leading skewed host tilting inflammation. Collectively, our study sheds light on virus-initiated ubiquitination pathway induces signaling provokes

Language: Английский

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Potent Antiviral Activity of Vitamin B12 against Severe Acute Respiratory Syndrome Coronavirus 2, Middle East Respiratory Syndrome Coronavirus, and Human Coronavirus 229E

Microorganisms, Journal Year: 2023, Volume and Issue: 11(11), P. 2777 - 2777

Published: Nov. 15, 2023

Repurposing vitamins as antiviral supporting agents is a rapid approach used to control emerging viral infections. Although there considerable evidence the use of vitamin supplementation in infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), specific role each defending against coronaviruses remains unclear. Antiviral activities available on infectivity and replication human coronaviruses, namely, SARS-CoV-2, Middle East (MERS-CoV), 229E (HCoV-229E), were investigated using silico vitro studies. We identified potential broad-spectrum inhibitor effects Hydroxocobalamin Methylcobalamin three tested CoVs. Cyanocobalamin could selectively affect SARS-CoV-2 but not MERS-CoV HCoV-229E. showed significantly higher inhibition values compared with Cyanocobalamin, while highest potent activity Furthermore, studies performed for these promising investigate their interaction MERS-CoV, HCoV-229E viral-specific cell receptors (ACE2, DPP4, hAPN protein, respectively) proteins (S-RBD, 3CL pro, RdRp), suggesting that Hydroxocobalamin, Methylcobalamin, may have significant binding affinity proteins. These results show benefits coronavirus-infected patients.

Language: Английский

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