Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect [scRNA-Seq 2]
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PROVIDER: PRJNA1284896 | ENA |
REPOSITORIES: ENA
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Project description:Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect
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Project description:Multiple mechanisms of immunity must be coordinated for the successful defense against a comprehensive range of pathogens, yet how broad-spectrum antipathogens act through these mechanisms remains largely elusive. Here, we used systems biology approaches to understand human immune cell reorganization at the single-cell level using a novel silane derivative, K21, which is effective against viruses, bacteria, and fungal infections. K21 significantly induced the differentiation of monocytes into macrophages and dendritic cells (MoDCs), as well as the differentiation of natural killer cells (NK cells). K21 decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, currently referred to as M4 macrophages, that play a critical role in solid cancers and fibrosis. K21-mediated immune cell remodeling was observed only in a complex multicellular co-culture environment, suggesting the interplay of various cell-derived components. K21 improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of mechanism. Our work demonstrates that a drug that remodels metabolism can shape the immune cell repertoire, which could help develop more effective antimicrobials and potentially prevent the development of drug-resistance pathogens.
2025-08-13 | GSE296571 | GEO
Project description:Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect [scRNA-Seq]
| PRJNA1284894 | ENA
Project description:Multiple mechanisms of immunity must be coordinated for the successful defense against a comprehensive range of pathogens, yet how broad-spectrum antipathogens act through these mechanisms remains largely elusive. Here, we used systems biology approaches to understand human immune cell reorganization at the single-cell level using a novel silane derivative, K21, which is effective against viruses, bacteria, and fungal infections. K21 significantly induced pro-inflammatory macrophages originating from both M1 and M2c macrophages without changing their ability to secrete respective cytokines. K21 decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, currently referred to as M4 macrophages, that play a critical role in solid cancers and fibrosis. K21-mediated immune cell remodeling was observed only in a complex multicellular co-culture environment, suggesting the interplay of various cell-derived components. K21 improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of the mechanism. Our work demonstrates that a drug that remodels metabolism can shape the immune cell repertoire, which could aid in the development of more effective antimicrobials and potentially prevent the emergence of drug-resistant pathogens.
2025-08-13 | GSE301383 | GEO
Project description:Multiple mechanisms of immunity must be coordinated for the successful defense against a comprehensive range of pathogens, yet how broad-spectrum antipathogens act through these mechanisms remains largely elusive. Here, we used systems biology approaches to understand human immune cell reorganization at the single-cell level using a novel silane derivative, K21, which is effective against viruses, bacteria, and fungal infections. K21 significantly induced pro-inflammatory macrophages originating from both M1 and M2c macrophages without changing their ability to secrete respective cytokines. K21 decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, currently referred to as M4 macrophages, that play a critical role in solid cancers and fibrosis. K21-mediated immune cell remodeling was observed only in a complex multicellular co-culture environment, suggesting the interplay of various cell-derived components. K21 improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of the mechanism. Our work demonstrates that a drug that remodels metabolism can shape the immune cell repertoire, which could aid in the development of more effective antimicrobials and potentially prevent the emergence of drug-resistant pathogens.
2025-08-13 | GSE301385 | GEO
Project description:Somatic hypermutation generates antibody specificities beyond the primary repertoire
| PRJNA1191854 | ENA
Project description:B cell somatic hypermutation (SHM) and selection in germinal centers (GCs) enhance antibody affinity for antigen. Here, we investigated whether SHM-based antibody evolution is restricted to specificities established through V(D)J recombination in the primary repertoire. Tracking pre-defined non-specific B cells across multiple immunization models revealed that non-cognate B cells within GCs undergo SHM. Under conditions of limited B cell competition, these B cells generated de novo antigen recognition to multiple epitopes across diverse model antigens. Phylogenetic analyses identified diverse mutational pathways leading to new antigen affinities, and enhanced T cell co-stimulation further promoted new antigen recognition. Our data support a model in which B cell competition-rather than an intrinsic requirement for specific affinity-limits the emergence of new affinities through SHM, highlighting the mammalian adaptive immune system's ability to explore antibody-antigen interactions beyond those encoded by the V(D)J-dependent primary repertoire, demonstrating the flexibility of SHM in not only ripening but also reshaping specificity.
2024-12-04 | GSE283094 | GEO
Project description:Our mucosal surfaces are the main sites of non-vector-borne pathogen entry, as well as the main interface with our commensal microbiota. We are still only beginning to understand how mucosal adaptive immunity interacts with commensal and pathogenic microbes to influence factors such as infectivity, phenotypic diversity, and within-host evolution. This is in part due to difficulties in generating specific mucosal adaptive immune responses without disrupting the mucosal microbial ecosystem itself. Here, we present a very simple tool to generate inactivated mucosal vaccines from a broad range of culturable bacteria. Oral gavage of 10(10) peracetic acid-inactivated bacteria induces high-titer-specific intestinal IgA in the absence of any measurable inflammation or species invasion. As a proof of principle, we demonstrate that this technique is sufficient to provide fully protective immunity in the murine model of invasive non-typhoidal Salmonellosis, even in the face of severe innate immune deficiency.
| S-EPMC4749699 | biostudies-literature
Project description:Random transposon mutagenesis is a powerful technique used to generate libraries of genetic insertions in many different bacterial strains. Here we develop a system facilitating random transposon mutagenesis in a range of different Gram-negative bacterial strains, including Pectobacterium atrosepticum, Citrobacter rodentium, Serratia sp. ATCC39006, Serratia plymuthica, Dickeya dadantii, and many more. Transposon mutagenesis was optimized in each of these strains and three studies are presented to show the efficacy of this system. Firstly, the important agricultural pathogen D. dadantii was mutagenized. Two mutants that showed reduced protease production and one mutant producing the previously cryptic pigment, indigoidine, were identified and characterized. Secondly, the enterobacterium, Serratia sp. ATCC39006 was mutagenized and mutants incapable of producing gas vesicles, proteinaceous intracellular organelles, were identified. One of these contained a β-galactosidase transcriptional fusion within the gene gvpA1, essential for gas vesicle production. Finally, the system was used to mutate the biosynthetic gene clusters of the antifungal, anti-oomycete and anticancer polyketide, oocydin A, in the plant-associated enterobacterium, Dickeya solani MK10. The mutagenesis system was developed to allow easy identification of transposon insertion sites by sequencing, after facile generation of a replicon encompassing the transposon and adjacent DNA, post-excision. Furthermore, the system can also create transcriptional fusions with either β-galactosidase or β-glucuronidase as reporters, and exploits a variety of drug resistance markers so that multiple selectable fusions can be generated in a single strain. This system of various transposons has wide utility and can be combined in many different ways.
| S-EPMC4686594 | biostudies-literature
Project description:Re-sequencing of the broad host-range IncP-alpha plasmid pRK404
| PRJEB36160 | ENA