Deciphering the role of peroxisomes in bacterial pathogenesis

项目摘要 传染病是全世界人类健康的主要威胁。的出现 抗生素抗性病原体需要开发新的药物来治疗感染。一 开发抗生素的根本挑战是许多病原体在宿主体内复制， 使它们无法接触到抗微生物剂。关键的流程， 宿主细胞内的病原体生长代表了治疗干预的有希望的新靶点。 大多数在宿主细胞内生长的细菌病原体都是在一个专门的隔室中生长的 叫做复制泡。维持复制泡的完整性对于 细菌的存活和生长，因为它提供了对宿主监视系统的保护， 检测和消除病原体。破坏这一过程将限制细菌的生长， 使宿主免疫系统能够杀死病原体。 最近，我们发现了宿主细胞过氧化物酶体与细胞凋亡之间前所未有的联系。 细菌病原体嗜肺军团菌维持其复制空泡的能力。的 在缺乏过氧化物酶体的情况下，军团菌的生长受损， 过氧化物酶体支持军团菌感染。过氧化物酶体在许多 细胞过程重要的是，过氧化物酶体因其关键的 在脂质的产生和分解中起作用，脂质是病原体复制的主要成分 液泡和细菌生长的营养源。这表明军团菌可能 利用过氧化物酶体来获取这些必需的分子。除了军团菌，许多 在宿主细胞内生长的病原体，使用共同的策略来建立感染， 特别是复制泡的形成和维持。因此过氧化物酶体很可能 对其他传染性细菌也很重要拟议的研究将确定如何 过氧化物酶体使军团菌能够致病，同时避免被发现， 身体的自然防御消除，这对新的发展至关重要。 抗生素

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.