Deciphering the role of peroxisomes in bacterial pathogenesis

破译过氧化物酶体在细菌发病机制中的作用

基本信息

批准号：
10595224
负责人：
Tamara O'Connor
金额：
$ 54.23万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2022-09-19 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595224
关键词：
Address Affect Alveolar Antibiotic Resistance Antibiotics Architecture Area Assimilations Bacteria Biochemistry Biogenesis Biology Cell physiology Cells Communicable Diseases Dependence Detection Development Disease Electron Microscopy Environment Exposure to Fatty Acids Fluorescence Microscopy Genes Genetic Goals Growth Health Homeostasis Hospitalization Human Immune Immune system Impairment Infection Inhalation Knowledge Lead Legionella Legionella pneumophila Legionellosis Life Link Lipids Lung Maintenance Membrane Membrane Proteins Metabolic Molecular Biology Techniques Molecular and Cellular Biology Nutrient Organelles Pathogenesis Pathway interactions Pharmaceutical Preparations Play Pneumonia Process Production Proteins Research Role Source System Therapeutic Intervention Vacuole Virulence Water Work antimicrobial drug biophysical properties contaminated water exposed human population fatty acid metabolism lipid metabolism man new therapeutic target novel therapeutics pathogen pathogenic bacteria peroxisome prevent programs recruit

项目摘要

PROJECT SUMMARY Infectious disease is a major threat to human health worldwide. The emergence of antibiotic resistance pathogens necessitates the development of new drugs to treat infections. A fundamental challenge in developing antibiotics is that many pathogens replicate inside host cells rendering them inaccessible to antimicrobial agents. The critical processes that govern pathogen growth within host cells represent promising new targets for therapeutic intervention. Most bacterial pathogens that grow inside host cells do so in a specialized compartment called the replication vacuole. Maintaining the integrity of the replication vacuole is critical to bacterial survival and growth as it provides protection against host surveillance systems that detect and eliminate pathogens. Disrupting this process would thus limit bacterial growth and enabling pathogen killing by the host immune system. Recently, we discovered an unprecedented link between host cell peroxisomes and the ability of the bacterial pathogen Legionella pneumophila to sustain its replication vacuole. The impaired growth of Legionella in the absence of peroxisomes demonstrates a critical role for peroxisomes in supporting Legionella infection. Peroxisomes play central roles in numerous cellular processes. Importantly, peroxisomes are most widely recognized for their critical functions in the production and breakdown of lipids, major constituents of pathogen replication vacuoles and sources of nutrients for growing bacteria. This suggests that Legionella may exploit peroxisomes to gain access to these essential molecules. In addition to Legionella, many pathogens that grow within host cells, use common strategies to establish an infection, in particular the formation and maintenance of a replication vacuole. Thus peroxisomes are likely to be important for other infectious bacteria. The proposed research will define how peroxisomes enable Legionella to cause disease while simultaneously avoiding detection and elimination by the body’s natural defenses, which is paramount to the development of new antibiotics.

项目概要传染病的出现是对全世界人类健康的重大威胁。抗生素耐药性病原体需要开发新药来治疗感染。抗生素发展的根本挑战是许多病原体在宿主体内复制细胞使其无法接触到抗菌剂。宿主细胞内病原体的生长代表了有希望的治疗干预新目标。大多数在宿主细胞内生长的细菌病原体是在专门的隔室中生长的称为复制液泡，保持复制液泡的完整性至关重要。细菌的生存和生长，因为它提供了针对宿主监视系统的保护检测并消除病原体将限制细菌的生长并减少细菌的生长。使宿主免疫系统能够杀死病原体。最近，我们发现宿主细胞过氧化物酶体和细菌病原体嗜肺军团菌维持其复制液泡的能力。在缺乏过氧化物酶体的情况下，军团菌的生长受损表明，过氧化物酶体在支持军团菌感染中发挥着核心作用。重要的是，过氧化物酶体因其关键作用而得到广泛认可。在脂质的产生和分解中发挥作用，脂质是病原体复制的主要成分液泡和细菌生长的营养来源这表明军团菌可能。利用过氧化物酶体来获取这些必需分子除了军团菌之外，还有许多细菌。在宿主细胞内生长的病原体，使用常见的策略来建立感染，特别是复制真空的形成和维持，因此过氧化物酶体很可能。对于其他传染性细菌来说很重要，拟议的研究将定义如何进行。过氧化物酶体使军团菌能够引起疾病，同时避免被发现和通过身体的自然防御消除，这对于新的开发至关重要抗生素。