A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling

Cell, Journal Year: 2022, Volume and Issue: 185(13), P. 2354 - 2369.e17

Published: May 13, 2022

Interferons (IFNs) induce an antimicrobial state, protecting tissues from infection. Many viruses inhibit IFN signaling, but whether bacterial pathogens evade responses remains unclear. Here, we demonstrate that the Shigella OspC family of type-III-secreted effectors blocks signaling independently its cell death inhibitory activity. Rather, inhibition was mediated by binding OspC1 and OspC3 to Ca2+ sensor calmodulin (CaM), blocking CaM kinase II downstream JAK/STAT signaling. The growth lacking attenuated in epithelial cells a murine model This phenotype rescued both models depletion receptors. homologs conserved additional not only bound also inhibited IFN, suggesting widespread virulence strategy. These findings reveal previously undescribed molecular mechanism critical role targeting pathogenesis.

Language: Английский

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Regulation of virulence in Chromobacterium violaceum and strategies to combat it

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 24, 2024

Chromobacterium is a rod-shaped, Gram-negative, facultatively anaerobic bacteria with cosmopolitan distribution. Just about 160 violaceum incidents have been reported globally, but then once infected, it has the ability to cause deadly septicemia, and infections in lungs, liver, brain, spleen, lymphatic systems that might lead death. C. produces utilizes violacein kill compete an ecological niche. Violacein hydrophobic bisindole delivered through efficient transport route termed outer membrane vesicles (OMVs) aqueous environment. OMVs are small, spherical segments detached from of Gram-negative bacteria. OMV secretions controlled by mechanism called quorum sensing system CviI / CviR , which enables cell-to-cell communication between them regulation various virulence factors such as biofilm formation, biosynthesis. Another factor bacterial type 3 secretion (T3SS) divided into two types: Cpi-1 Cpi-2 . ’s needle rod effector proteins perhaps recognized NAIP receptors humans mice, activating NLRC4 inflammasome cascade, effectively clearing spleen via pyroptosis, cytotoxicity mediated IL-18-driven Natural killer (NK) cells liver. In this paper, we attempt interrelate quorum-controlled production, delivery T3SS protein production host immunological effects against Cpi1 T3SS. We suggest research path natural bioactive molecule like palmitic acid can act anti-quorum agent reducing expression well immunomodulatory augment innate immune defense hyperactivation hence dramatically purge infections.

Language: Английский

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Shigella induces stress granule formation by ADP-riboxanation of the eIF3 complex

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113789 - 113789

Published: Feb. 1, 2024

Under stress conditions, translationally stalled mRNA and associated proteins undergo liquid-liquid phase separation condense into cytoplasmic foci called granules (SGs). Many viruses hijack SGs for their pathogenesis; however, whether pathogenic bacteria also exploit this pathway remains unknown. Here, we report that members of the OspC family Shigella flexneri induce SG formation in infected cells. Mechanistically, effectors target multiple subunits host translation initiation factor 3 complex by ADP-riboxanation. The modification eIF3 leads to translational arrest thus SGs. Furthermore, OspC-mediated are beneficial S. replication within cells, bacterial strains unable attenuated virulence a murine model infection. Our findings reveal mechanism which pathogens assembly inactivating machinery promote proliferation

Language: Английский

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Structural mechanisms of calmodulin activation of Shigella effector OspC3 to ADP-riboxanate caspase-4/11 and block pyroptosis

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(3), P. 261 - 272

Published: Jan. 9, 2023

Language: Английский

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An innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2

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

Published: Oct. 21, 2023

Abstract Granulomas often form around pathogens that cause chronic infections. Here, we discover an innate granuloma model in mice with environmental bacterium called Chromobacterium violaceum . Granuloma formation not only successfully walls off, but also clears, the infection. The infected lesion can arise from a single replicates despite presence of neutrophil swarm. Bacterial replication ceases when macrophages organize infection and granuloma. This response is accomplished independently adaptive immunity typically required to granulomas. C. -induced requires at least two separate defense pathways, gasdermin D iNOS, maintain integrity architecture. eradicates Therefore, this demonstrates immune cells thereby resolve by pathogen.

Language: Английский

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Mechanism of the Mongolian medicine Eerdun Wurile basic formula in improving postoperative cognitive dysfunction by inhibiting apoptosis through the SIRT1/p53 signaling pathway

Journal of Ethnopharmacology, Journal Year: 2023, Volume and Issue: 309, P. 116312 - 116312

Published: Feb. 28, 2023

The Mongolian medicine Eerdun Wurile is a commonly used in folk to treat cerebral nervous system diseases such as hemorrhage, thrombosis, nerve injury and cognitive function, cardiovascular hypertension coronary heart disease. wurile may effect anti-postoperative function.To investigate the molecular mechanism of Basic Formula (EWB) improving postoperative dysfunction (POCD) based on Network pharmacology, confirm involvement SIRT1/p53 signal pathway, one key pathways, by using POCD mouse model.Obtain compounds disease-related targets through TCMSP, TCMID, PubChem, PharmMapper platforms, GeneCards, OMIM databases, screen intersection genes; Use Cytoscape software build "drug-ingredient-disease-target" network, STRING platform for protein interaction analysis.; R was analyze function gene ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) enrichment.; AutoDock Vina active components core Perform docking. model prepared intracerebroventricular injection lipopolysaccharide (LPS), morphological changes hippocampal tissue were observed hematoxylin-eosin (HE) staining, Western blot, immunofluorescence TUNEL verify results network pharmacological enrichment analysis.There 110 potential EWB, 117 items enriched GO, 113 pathways KEGG, among which signaling pathway related occurrence POCD. Quercetin, kaempferol, vestitol, β-sitosterol 7-methoxy-2-methyl isoflavone EWB can form stable conformations with low binding energy target proteins IL-6, CASP3, VEGFA, EGFR ESR1. Animal experiments showed that compared group, group could significantly improve apoptosis hippocampus mice, down-regulate expression Acetyl-p53 (P < 0.05).EWB characteristics multi-component, multi-target, multi-pathway synergistic effects. Studies have confirmed regulating genes provides new basis treatment

Language: Английский

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Bisphenol a Disrupts Steroidogenesis and Induces Apoptosis in Human Granulosa Cells Cultured In Vitro

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4081 - 4081

Published: April 25, 2025

Bisphenol A (BPA) is a common synthetic chemical compound classified as an endocrine disruptor. It affects multiple physiological systems in the body, including female reproductive system, particularly granulosa cells (GCs) ovaries, where steroidogenesis occurs. This study investigated impact of various BPA concentrations (environmentally relevant 0.001 µM and 0.1 toxicological concentration 100 µM) exposure times (24 72 h) on cell viability counts vitro production estradiol progesterone human GCs collected from waste follicular fluid IVF patients. Gene expression analysis 182 genes associated with apoptosis was performed using PCR arrays, followed by protein Western blot. Our results demonstrate that after longer (72 h), higher (100 negatively cellular significantly alters steroid hormone biosynthesis vitro, leading to reduced culture medium. We found all altered different steroidogenesis- apoptosis-related GCs. At μM, decreased TRIM25, UGT2B15, CASP3, RPS6KA3 increased NR6A1 PPID genes. AR, HSD3B1, BID, IKBKG, while reducing TRIM25 CASP3 highest upregulated GPER30, downregulated FOXO1 UGT2B15 These highlight BPA’s concentration-specific effects show its potential compromise GC function, possible negative implications for fertility ovarian health, even at environmentally concentrations.

Language: Английский

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Non-Canonical Inflammasome Pathway: The Role of Cell Death and Inflammation in Ehrlichiosis

Cells, Journal Year: 2023, Volume and Issue: 12(22), P. 2597 - 2597

Published: Nov. 9, 2023

Activating inflammatory caspases and releasing pro-inflammatory mediators are two essential functions of inflammasomes which triggered in response to pathogen-associated molecular patterns (PAMPs) or danger-associated (DAMPs). The canonical inflammasome pathway involves the activation its downstream via adaptor ASC protein, causes caspase 1 and, eventually, cleavage pro-IL-1b pro-IL-18. non-canonical is induced upon detecting cytosolic lipopolysaccharide (LPS) by NLRP3 Gram-negative bacteria. triggers murine 11 (human 4 5), results formation pores (via gasdermin) cause pyroptosis. Ehrlichia an obligately intracellular bacterium responsible for causing human monocytic ehrlichiosis (HME), a potentially lethal disease similar toxic shock syndrome septic syndrome. Several studies have indicated that crucial pathogenic mechanism induces dysregulated inflammation host cellular death pathophysiology HME. Mechanistically, pathways affected virulent infection due block autophagy. This review aims explore significance ehrlichiosis, how involving (with exception 1) contribute severe fatal ehrlichiosis. Improving our understanding cell will help advancement innovative therapeutic, preventative, diagnostic approaches treatment

Language: Английский

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Ca2+-calmodulin signalling at the host-pathogen interface

Current Opinion in Microbiology, Journal Year: 2023, Volume and Issue: 72, P. 102267 - 102267

Published: Jan. 28, 2023

Multiple eukaryotic cell processes are modulated by calcium ions (Ca2+). As such, Ca2+ is emerging as a crucial regulator of innate immunity in multicellular organisms. In particular, recent studies have identified roles signalling at the host-bacteria interface. Following microbial exposure, signals mobilised from extracellular milieu or intracellular stores transduced into physiological responses. However, during infection with host-adapted pathogens, often atypical, due to activities virulence factors, varied consequences for both pathogen and host cell. this review, we describe Ca2+-dependent factors regulating antibacterial immunity, addition bacterial effectors that promote, inhibit, co-opt Ca2+-calmodulin promote infection.

Language: Английский

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Pyroptosis modulation by bacterial effector proteins

Seminars in Immunology, Journal Year: 2023, Volume and Issue: 69, P. 101804 - 101804

Published: July 3, 2023

Language: Английский

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