Viroporin activity is necessary for intercellular calcium signals that contribute to viral pathogenesis

Science Advances, Journal Year: 2025, Volume and Issue: 11(3)

Published: Jan. 17, 2025

Viruses engage in a variety of processes to subvert host defenses and create an environment amenable replication. Here, using rotavirus as prototype, we show that calcium conductance out the endoplasmic reticulum by virus encoded ion channel, NSP4, induces intercellular waves extend beyond infected cell contribute pathogenesis. lack ability induce this signaling diminished viral shedding attenuated disease mouse model diarrhea. This implicates nonstructural protein 4 (NSP4) virulence factor provides mechanistic insight into its mode action. Critically, transcriptional signature characteristic interferon-independent innate immune activation, which is not observed response mutant NSP4 does conduct calcium. dysregulation means pathogen recognition, theme broadly applicable calcium-altering pathogens rotavirus.

Language: Английский

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Identification, Quantification, and Characterization of HIV-1 Reservoirs in the Human Brain

Cells, Journal Year: 2022, Volume and Issue: 11(15), P. 2379 - 2379

Published: Aug. 2, 2022

The major barrier to cure HIV infection is the early generation and extended survival of reservoirs in circulation tissues. Currently, techniques used detect quantify are mostly based on blood-based assays; however, it has become evident that viral remain Our study describes a novel multi-component imaging method (HIV DNA, mRNA, proteins same assay) identify, quantify, characterize tissues blood products obtained from HIV-infected individuals even when systemic replication undetectable. In human brains under ART, we identified microglia/macrophages small population astrocytes main cells with integrated DNA. Only half DNA expressed one-third proteins. Surprisingly, residual HIV-p24, gp120, nef, vpr, tat protein expression accumulation uninfected around suggesting local synthesis, secretion, bystander uptake. conclusion, our data show ART reduces size brain’s reservoirs; local/chronic secretion still occurs, indicating brain anatomical target infection.

Language: Английский

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The Role of Connexin Hemichannels in Inflammatory Diseases

Biology, Journal Year: 2022, Volume and Issue: 11(2), P. 237 - 237

Published: Feb. 2, 2022

The connexin protein family consists of approximately 20 members, and is well recognized as the structural unit gap junction channels that perforate plasma membranes coupled cells and, thereby, mediate intercellular communication. Gap junctions are assembled by two preexisting hemichannels on apposing cells. Non-junctional (CxHC) provide a conduit between cell interior extracellular milieu, believed to be in protectively closed state under physiological conditions. development characterization peptide mimetics amino acid sequences connexins have resulted panel blockers with higher selectivity for CxHC, which become important tools defining role CxHC various biological processes. It increasingly clear can induced open pathogen-associated molecular patterns. opening facilitates release damage-associated patterns, class endogenous molecules critical pathogenesis inflammatory diseases. blockade leads attenuated inflammation, reduced tissue injury improved organ function human animal models about thirty diseases disorders. These findings demonstrate may contribute intensification serve common target treatments In this review, we an update progress understanding focus these

Language: Английский

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Mechanisms of HIV-mediated blood-brain barrier compromise and leukocyte transmigration under the current antiretroviral era

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109236 - 109236

Published: Feb. 15, 2024

HIV-associated neurological compromise is observed in more than half of all people with HIV (PWH), even under antiretroviral therapy (ART). The mechanism has been associated the early transmigration HIV-infected monocytes across BBB a CCL2 and replication-dependent manner. However, mechanisms chronic brain damage are unknown. We demonstrate that PWH ART have elevated circulating ATP levels correlate onset cognitive impairment absence virus. Serum found most severe neurocognitive trigger transcellular migration leukocytes JAM-A LFA-1-dependent propose targeting leukocyte could reduce or prevent devastating consequences within brains ART.

Language: Английский

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Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Feb. 19, 2024

The coronavirus disease 2019 (COVID-19) pandemic triggered an unprecedented concentration of economic and research efforts to generate knowledge at unequalled speed on deregulated interferon type I signalling nuclear factor kappa light chain enhancer in B-cells (NF-κB)-driven interleukin (IL)-1β, IL-6, IL-18 secretion causing cytokine storms. translation the how resulting systemic inflammation can lead life-threatening complications into novel treatments vaccine technologies is underway. Nevertheless, previously existing role cytoplasmatic or circulating self-DNA as a pro-inflammatory damage-associated molecular pattern (DAMP) was largely ignored. Pathologies reported ‘ de novo ’ for patients infected with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 be outcomes self-DNA-driven fact had been linked earlier different contexts, e.g., infection Human Immunodeficiency Virus (HIV)-1, sterile inflammation, autoimmune diseases. highlight particularly synergies other DAMPs render immunogenic properties normally non-immunogenic extracellular self-DNA, discuss shared features gp41 unit HIV-1 envelope protein SARS-CoV 2 Spike that enable SARS-CoV-2 interact cell membranes, trigger syncytia formation, inflict damage their host’s DNA, – likely own benefit. These similarities motivate speculations similar mechanisms those driven by explain inflammatory contributes some most frequent adverse events after vaccination BNT162b2 mRNA (Pfizer/BioNTech) mRNA-1273 (Moderna) vaccine, i.e., myocarditis, herpes zoster, rheumatoid arthritis, nephritis hepatitis, new-onset lupus erythematosus, flare-ups psoriasis lupus. hope wider application lessons learned from experiences COVID-19 new vaccines combat future non-COVID-19

Language: Английский

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Inactivated SARS-CoV-2 induces acute skeletal muscle damage in human K18-hACE2 transgenic mice

Life Sciences, Journal Year: 2025, Volume and Issue: unknown, P. 123404 - 123404

Published: Jan. 1, 2025

Language: Английский

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Pharmacological mechanisms of probenecid for SARS-CoV-2 and RSV co-infection: findings of system pharmacology, molecular docking, molecular dynamics simulation, and structure–activity relationship

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

Published: April 30, 2025

The clinical consequences of the co-infection with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and syncytial virus (RSV) are not optimistic. Nevertheless, there is currently no approved therapeutic regimen specifically targeting SARS-CoV-2/RSV co-infection, existing monotherapies showing limited efficacy. According to recent studies, probenecid has both anti-SARS-CoV-2 anti-RSV effects. Therefore, as one probable molecular candidate for SARS-CoV-2 RSV, was researched in this exploration. Using systems pharmacology bioinformatics, we characterized targets associated treatment focusing on their biological functions, mechanisms binding activities. To further validate these findings, conducted docking, MD simulations, electrostatic potential mapping, SAR analysis explore interactions between identified core targets. We 141 that overlapped probenecid, used shared construct a protein-protein interaction (PPI) network. Subsequently, obtained top 16 hub namely, AKT1, ALB, EGFR, CASP3, CTNNB1, SRC, HSP90AA1, so on. enrichment analysis, might affect inflammation, immunity, oxidative stress, defenses; Toll-like receptor, TNF, IL-17, NOD-like cytokine-cytokine among others. Additionally, based docking effectively bound related co-infection. Meanwhile, according dynamics (MD) simulations structure-activity relationship (SAR) speculated SRC HSP90AA1 more likely be target proteins than other proteins. Our findings from bioinformatics indicate immune inflammatory responses play pivotal role effects probenecid. Infectious disease-related pathways also contribute significantly its effectiveness treating Further validation through analysis. These analyses suggest This study provides valuable preliminary insights into It establishes strong foundation future research strategy

Language: Английский

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Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication

Viruses, Journal Year: 2022, Volume and Issue: 14(3), P. 612 - 612

Published: March 15, 2022

Viral replication and transmissibility are the principal causes of endemic pandemic disease threats. There remains a need for broad-spectrum antiviral agents. The most common respiratory viruses agents such as coronaviruses, syncytial viruses, influenza viruses. Although vaccines available SARS-CoV-2 some there is paucity effective drugs, while RSV no vaccine available, therapeutic treatments very limited. We have previously shown that probenecid safe in limiting A virus replication, along with strong evidence showing inhibition vitro vivo. This review article will describe activity profile against these three

Language: Английский

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Drug repurposing for cardiovascular diseases: New targets and indications for probenecid

British Journal of Pharmacology, Journal Year: 2022, Volume and Issue: 180(6), P. 685 - 700

Published: Dec. 9, 2022

The available pharmacological options in the management of cardiovascular diseases such as ischaemic heart disease and subsequent failure are effective slowing progression this condition. However, long‐term prognosis is still poor, raising demand for new therapeutic strategies. Drug repurposing a time‐ cost‐effective drug development strategy that offers approved abandoned drugs chance indications. Recently, used gout‐related inflammation canakinumab or colchicine have been considered old uricosuric drug, probenecid, has identified novel option specific cardiac well. Probenecid can modulate myocardial contractility vascular tone exerts anti‐inflammatory properties. mechanisms behind these beneficial effects might be related inhibition inflammasomes, to modulation purinergic–pannexin‐1 signalling TRPV2 channels, which recently molecular targets probenecid. In review, we provide an overview on probenecid by summarizing experimental clinical data propose its potential treat diseases.

Language: Английский

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Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis

Cell Calcium, Journal Year: 2022, Volume and Issue: 106, P. 102637 - 102637

Published: Aug. 11, 2022

Language: Английский

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