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Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation

ABSTRACT: Resistance, tolerance and persistence enable pathogenic bacteria to survive antibiotic treatment and are associated with an elevated risk of treatment failure and relapsing infections. The mechanism underlying bacterial antibiotic persister formation is not well understood. Here, we show that glyoxylate, a metabolite originally evolved to allow bacteria to utilize alternative carbon sources for optimal growth and pathogenicity, also serves as a signaling molecule to alter host gene expression and support persister formation. Specifically, we discovered glyoxylate interacting with TET2 DNA dioxygenase through an in-silico screen of human metabolome. We further show that Salmonella-produced glyoxylate inhibits the activity of Tet2 to suppress the expression of pro-inflammatory genes and attenuate host immune defense. Catalytic inactivation of Tet2, by genetic knock-in mutation, glyoxylate production by Salmonella, or exogenous glyoxylate treatment, facilitates bacterial persister formation in both murine and human macrophages. Conversely, stimulating TET2 with vitamin C or blocking Salmonella production of glyoxylate counters bacterial antibiotic resistance and improves the infection treatment outcomes. In conclusion, our study reveals a novel signaling function of glyoxylate in gene regulation beyond energetic and biosynthetic metabolism. Our findings also suggest that stimulating TET activity within host cells represents a potential therapeutic strategy to combat bacterial persistence.

ORGANISM(S): Mus musculus

PROVIDER: GSE281447 | GEO | 2024/11/13

REPOSITORIES: GEO

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Project description:Kaiser2014 - Salmonella persistence after ciprofloxacin treatment The model describes the bacterial tolerance to antibiotics. Using a mouse model for Salmonella diarrhea, the authors have found that bacterial persistence occurs in the presence of the antibiotic ciprofloxacin because Salmonella can exist in two different states. One, the fast-growing population that spreads in the host's tissues and the other, slow-growing "persister" population that hide out inside dendritic cells of the host's immune system and cannot be attacked by the antibiotics. However, this can be killed by adding agents that directly stimulate the host's immune defense. This model is described in the article: Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment. Kaiser P, Regoes RR, Dolowschiak T, Wotzka SY, Lengefeld J, Slack E, Grant AJ, Ackermann M, Hardt WD. PLoS Biol. 2014 Feb 18;12(2):e1001793. Abstract: In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%-20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics. This model is hosted on BioModels Database and identified by: MODEL1312170001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation

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