Neisseria gonorrhoeae central metabolism in the context of neutrophilic inflammation

中性粒细胞炎症背景下淋病奈瑟菌的中枢代谢

基本信息

批准号：
10364695
负责人：
Alison K Criss
金额：
$ 20.19万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-04 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10364695
关键词：
Address Affect Algorithms Antibiotic Resistance Antibiotics Bacteria Biochemical Pathway Biomass Carbon Centers for Disease Control and Prevention (U.S.)Cessation of life Citric Acid Cycle Clinical Coculture Techniques Computer Models Consumption Data Data Set Development Disease Enzymes Exposure to Exudate Future GC gene Gene Expression Genes Glucose Glycolysis Gonorrhea Growth Health Human Immune Immune response Immunity Immunology Infection Infertility Inflammation Inflammatory Response Investigation Iron Knock-out Knowledge Lead Literature Measures Metabolic Metabolic Pathway Metabolism Metals Modeling Mucous Membrane Mutation Names Neisseria gonorrhoeae Nutrient Nutritional Immunity Outcome Pathogenesis Pathway interactions Persons Phagocytosis Population Prevalence Production Proteins Public Health Pyruvate Reaction Reactive Oxygen Species Reporting Research Research Personnel Sexually Transmitted Agents Sexually Transmitted Diseases Source Superbug Supplementation Surface Systems Biology Testing Therapeutic Time Transcript Vaccines Virulence Zinc antimicrobial antimicrobial peptide bacterial genetics bacterial metabolism chronic pelvic pain cohort flexibility genetic information genetic linkage genome-wide genome-wide analysis inflammatory milieu innovation metabolic abnormality assessment microbial mutant neutrophil pathogen predictive modeling reconstruction reproductive resistant strain response transcriptome sequencing transcriptomics transposon sequencing uptake

项目摘要

ABSTRACT Neisseria gonorrhoeae (Gc) is the causative agent of the sexually transmitted disease gonorrhea. Gc is a prominent threat to human health due to emergence of “superbug” strains that are resistant to all current antibiotics and its clinical sequelae, including infertility and chronic pelvic pain, that have severe and lifelong effects. Gc is highly adapted to colonize human mucosal surfaces, where it survives despite initiating a robust inflammatory response and influx of polymorphonuclear leukocytes (PMNs or neutrophils) that typically clear bacteria. We recently used the unbiased, genome-wide approaches of transposon-sequencing and dual RNA- sequencing of Gc and PMNs to identify a cohort of genes contributing to successful Gc infection of PMNs. Gc metabolic genes were overrepresented in this cohort, suggesting that Gc utilizes distinct metabolic pathways to circumvent human mucosal defenses. We have applied this information to systems biology approaches to generate a preliminary metabolic network reconstruction for Gc. This analysis leads to the prediction that Gc utilizes specific host-derived metabolites to fuel its metabolism – in particular, lactate. PMNs are highly glycolytic and consequently secrete lactate. Lactate can be consumed by Gc and is known to stimulate Gc glycolysis. Thus we hypothesize that Gc exploits PMN metabolism, specifically lactate secretion, to survive at mucosal surfaces. In this proposal, we will identify the central carbon metabolic pathways used by Gc in the presence of neutrophils, using a combination of metabolite analysis, metabolic modeling, and bacterial genetic knockouts in Gc metabolic enzymes. We will then test the necessity of these metabolic pathways in Gc for enhancing bacterial survival from neutrophils and the underlying mechanisms, including modulating neutrophil antimicrobial responses, changing Gc sensitivity to neutrophil antimicrobial components, and/or circumventing host nutritional immunity, or modulating neutrophil antimicrobial responses. Together, this proposal will address key gaps in knowledge of the fundamental metabolic processes of Gc during infection that are likely to have major impacts on outcomes of gonorrhea.

抽象的淋病奈瑟氏菌（GC）是性传播疾病淋病的病因。 GC是一个由于出现了对所有当前的“超级咬合”菌株的出现，对人类健康的重大威胁抗生素及其临床后遗症，包括不育和慢性骨盆疼痛，患有严重和终身的后遗症效果。 GC高度适应性地殖民人粘膜表面，生存下来的承诺会启动强大多形核白细胞（PMN或中性粒细胞）的炎症反应和影响通常清除细菌。我们最近使用了跨底座子测序和双重RNA-的无偏见的全基因组方法 GC和PMN的测序以确定导致PMN成功GC感染的基因组。 GC 代谢基因在该队列中的代谢过多，这表明GC利用了不同的代谢途径规避人粘膜防御。我们已将这些信息应用于系统生物学方法为GC生成初步的代谢网络重建。该分析导致了一个预测GC 利用特定的宿主代谢物来促进其代谢，尤其是裂缝。 PMN高糖酵解因此分泌裂缝。乳酸可以用GC消耗，众所周知会刺激GC糖酵解。那我们假设GC利用PMN代谢，特别是分泌物，以在粘膜表面生存。在此提案中，我们将确定GC在存在中性粒细胞的情况下使用的中央碳代谢途径，使用代谢物分析，代谢建模和GC代谢中的自由基敲除的组合酶。然后，我们将测试GC中这些代谢途径的必要条件，以增强来自中性粒细胞和潜在机制，包括调节中性粒细胞抗菌反应，改变对中性粒细胞抗菌成分的GC敏感性和/或避免宿主营养免疫，或调节中性粒细胞抗菌反应。该提议将共同解决知识的关键差距感染期间GC的基本代谢过程可能对结果产生重大影响淋病。