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.

项目摘要 传染病是全球人类健康的主要威胁。出现 抗生素耐药性病原体需要开发新药来治疗感染。一个 开发抗生素的基本挑战是许多病原体在宿主内部复制 细胞使它们无法访问抗菌剂。病原体的关键过程 宿主细胞的生长是治疗干预的最有希望的新靶标。 大多数在宿主细胞内生长的细菌病原体都在专门的隔室中进行 称为复制液泡。复制液泡的形成和维护是 对细菌生存和生长的重要性，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，并使宿主杀死病原体。尽管至关重要 复制液泡生物发生的作用，造成的机制知之甚少。 确定病原体如何产生和维持复制的主要障碍 液泡是冗余。细菌通过将细菌蛋白分泌到成像中形成复制液泡 宿主细胞调节各种宿主生物学过程。而分泌机械 本身对于疾病至关重要，个体分泌的蛋白质是可分配的。这通常发生 因为一种分泌蛋白的活性可以补偿另一种蛋白质的损失。然而， 许多病原体还采用多种策略来产生复制液泡。 冗余使得定义个体分泌蛋白在疾病中的作用非常困难 因此，确定新抗生素的有希望的靶标。 我们已经开发了一种基因筛查技术来解决之间的冗余 细菌病原体的分泌蛋白质，是威胁生命的原因 肺炎。我们已经定义了一组分泌的蛋白质，这些蛋白质有助于相同的策略 复制液泡形成和用于实现这一目标的单独但多余的策略 任务。这项研究的目的是确定单个组件如何构成 单一策略促进复制液泡形成，独立策略如何贡献 这个过程以及它们如何互补。这项工作将提供前所未有的 深入了解确定感染结果的关键事件和开发新的手段 预防和治疗疾病的策略。