Defining redundant strategies central to Legionella replication vacuole formation

定义对军团菌复制液泡形成至关重要的冗余策略

• 批准号: 9156146
• 负责人: Tamara O'Connor
• 金额: $ 38.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9156146
• 关键词: Alveolar Macrophages; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Proteins; Binding; Biochemical; Biochemistry; Biogenesis; Biological Assay; Biological Process; Breathing; Cell Death; Cell physiology; Cells; Cellular biology; Communicable Diseases; Complex; DNA Sequence Alteration; Defect; Development; Disease; Environment; Event; Exposure to; Genetic; Genetic Screening; Goals; Growth; Health; Hospitalization; Human; Immune; Individual; Infection; Insertional Mutagenesis; Lead; Legionella; Legionella pneumophila; Legionellosis; Life; Lung; Maintenance; Maps; Membrane; Nutrient; Organelles; Outcome; Parasites; Pathogenesis; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Pneumonia; Process; Proteins; Research; Role; Set protein; Source; System; Techniques; Therapeutic Intervention; Vacuole; Variant; Virulence; Water; Work; antimicrobial drug; arm; contaminated water; exposed human population; functional group; insight; killings; man; novel; novel therapeutics; paralogous gene; pathogen; prevent; screening; trafficking

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 infection. A fundamental challenge in developing antibiotics is that many pathogens replicate inside host cells rendering them inaccessible to antimicrobial agents. Critical processes for pathogen growth in host cells represent the most promising new targets for therapeutic intervention. Most bacterial pathogens that grow inside host cells do so in a specialized compartment called the replication vacuole. The formation and maintenance of a replication vacuole are paramount to bacterial survival and growth as it provides a source of nutrients and protection against host surveillance systems that detect and eliminate pathogens. Disrupting this process would thus limit bacterial burden and enabling pathogen killing by the host. Despite the crucial role of replication vacuole biogenesis, the mechanisms responsible are poorly understood. A major obstacle in determining how a pathogen generates and sustains a replication vacuole is redundancy. Bacteria form a replication vacuole by secreting bacterial proteins into the host cell to modulate a variety of host biological processes. While the secretion machinery itself is essential for disease, individual secreted proteins are dispensable. This often occurs because the activity of one secreted protein can compensate for the loss of another. However, many pathogens also employ multiple strategies for generating a replication vacuole. Redundancy makes it very difficult to define the roles of individual secreted proteins in disease and thus, identify promising targets for new antibiotics. We have developed a genetic screening technique to resolve redundancy amongst secreted proteins of the bacterial pathogen Legionella, the cause of a life-threatening pneumonia. We have defined sets of secreted proteins that contribute to the same strategy in replication vacuole formation and separate but redundant strategies used to accomplish this task. The goal of this research is to determine how individual components that constitute a single strategy promote replication vacuole formation, how independent strategies contribute to this process and how they compensate for one another. This work will provide unprecedented insight into a critical event determining the outcome of an infection and a means to develop new strategies to prevent and treat disease.

项目概要 传染病是全世界人类健康的主要威胁。的出现 抗生素耐药性病原体需要开发新药来治疗感染。一个 开发抗生素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。病原体的关键过程 宿主细胞的生长代表了最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。复制液泡的形成和维持是 对于细菌的生存和生长至关重要，因为它提供了营养和保护的来源 针对检测和消除病原体的宿主监视系统。破坏这个过程 因此将限制细菌负担并使得宿主能够杀死病原体。尽管至关重要 尽管复制液泡生物发生的作用，但其机制尚不清楚。 确定病原体如何产生和维持复制的主要障碍 液泡是冗余的。细菌通过将细菌蛋白分泌到复制液中形成复制液泡 宿主细胞调节多种宿主生物过程。而分泌机器 其本身对于疾病来说是必需的，个体分泌的蛋白质是可有可无的。这种情况经常发生 因为一种分泌蛋白的活性可以补偿另一种分泌蛋白的损失。然而， 许多病原体还采用多种策略来产生复制液泡。 冗余使得很难定义单个分泌蛋白在疾病中的作用 从而确定新抗生素的有希望的目标。 我们开发了一种基因筛查技术来解决基因组之间的冗余问题 细菌病原体军团菌的分泌蛋白，这是危及生命的原因 肺炎。我们已经定义了一组分泌蛋白，它们有助于相同的策略 复制液泡的形成和用于实现这一目标的单独但冗余的策略 任务。这项研究的目的是确定构成一个系统的各个组件如何 单一策略促进复制液泡形成，独立策略如何促进 这一过程以及它们如何相互补偿。这项工作将提供前所未有的 深入了解决定感染结果的关键事件以及开发新方法 预防和治疗疾病的策略。