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The roles of glutathione metabolism in growth and virulence of Listeria monocytogenes

谷胱甘肽代谢在单核细胞增生李斯特菌生长和毒力中的作用

基本信息

批准号：
10671070
负责人：
BORIS R BELITSKY
金额：
$ 24.75万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671070
关键词：
Address Affect Amino Acids Animals Bacteria Biochemical Cells Cysteine Cytosol Degradation Pathway Dependence Development Disease Drug Metabolic Detoxication Elderly Environment Enzymes Essential Amino Acids Eukaryotic Cell Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Genetic Screening Genetic Transcription Genome Glutathione Glutathione Metabolism Pathway Gram-Positive Bacteria Growth Human Immunocompromised Host In Vitro Individual Infection Knowledge Listeria monocytogenes Maintenance Metabolic Metabolic Pathway Metabolism Modeling Mus Nature Newborn Infant Oral Organism Oxidation-Reduction Pathogenesis Pathogenicity Pathway interactions Peptides Physiological Pregnant Women Proteins Regulation Research Role Signal Transduction Source Testing Therapeutic Intervention Toxic effect United States Virulence Virulence Factors Virulent extracellular foodborne foodborne illness foodborne infection foodborne pathogen mouse model novel novel therapeutics oxidation pathogen pathogenic bacteria response transcription factor transposon sequencing uptake virulence gene

项目摘要

ABSTRACT Listeria monocytogenes is a low G+C Gram-positive bacterium that can cause severe disease in immunocompromised individuals, pregnant women, newborns, and the elderly. Pathogenic listerial strains use a master transcriptional regulator, PrfA, to induce its most important virulence genes. In turn, the PrfA protein is directly activated by glutathione, a cysteine-containing tripeptide, which also performs important antioxidation and detoxification functions in bacterial and eukaryotic cells. To reach the intracellular level of glutathione required for sufficient PrfA activation and virulence gene expression during infection, the listerial cells need either to synthesize glutathione or import it from the cytosol of host cells, which is rich in glutathione. Surprisingly, listerial glutathione synthesis appears to contribute more strongly to virulence than its uptake from the eukaryotic cytosol. Glutathione uptake pathways have been identified only in several bacterial species; the L. monocytogenes glutathione importer(s) and the reasons for their apparent low activity during infection are not known. To synthesize glutathione and just to grow, L. monocytogenes cells must obtain cysteine, an essential amino acid, or a related compound from the environment. Interestingly, listerial cells can convert efficiently exogeneous glutathione to cysteine. This glutathione degradation, depending on the yet unknown extracellular or intracellular localization of this pathway, can reduce the metabolite level in bacterial or host cells or both. Therefore, a tight regulation of glutathione degradation may be a critical step in listerial virulence during infection. The glutathione-to-cysteine degradation pathway in L. monocytogenes has not been identified, and none of the genes encoding known enzymes of glutathione cleavage are present in the listerial genome. Thus, a novel enzyme of glutathione degradation with an unknown cellular localization is present in listerial cells. The complete lack of information on the nature of the glutathione uptake and degradation pathways, their regulation, and contributions to the glutathione level and PrfA activation impedes our understanding of how virulence genes are induced under various conditions of listerial growth. We propose to fill this important gap in our knowledge and determine the L. monocytogenes genes that are involved in the uptake and degradation of glutathione. Expression patterns of these genes under various growth conditions will be determined. The impact of the corresponding pathways on the glutathione listerial pool, expression of PrfA- dependent virulence genes, and virulence in a mouse model of infection will be major targets of our research. L. monocytogenes is one of the deadliest foodborne pathogens in the United States. This project will allow us to identify metabolic steps required for the accumulation of glutathione at levels that are needed for listerial virulence. In doing so, we may uncover novel pathways for potential therapeutic intervention. Similar pathways are likely to exist in other pathogenic bacteria.

摘要