Deciphering the role of peroxisomes in bacterial pathogenesis

项目总结 传染病是世界范围内对人类健康的主要威胁。新技术的出现 抗生素耐药病原体需要开发治疗感染的新药。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 使它们不能被抗菌剂接触到的细胞。治理的关键过程 病原体在宿主细胞内的生长是治疗干预的新靶点。 大多数生长在宿主细胞内的细菌病原体都是在一个专门的隔间里生长的 被称为复制液泡。保持复制空泡的完整性对于 细菌的生存和生长，因为它提供了对宿主监视系统的保护 检测和消除病原体。破坏这一过程会因此限制细菌的生长和 能够通过宿主免疫系统杀死病原体。 最近，我们发现了宿主细胞过氧化酶体和细胞外基质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。这个 在没有过氧化物体的情况下军团菌的生长受阻表明了 过氧化体在支持军团菌感染中的作用。过氧酶体在许多 细胞过程。重要的是，过氧化物酶体最广为人知的是它们的关键 在病原体复制的主要成分--脂类的产生和分解中的作用 液泡和生长细菌的营养来源。这表明军团菌可能 利用过氧化物体来获得这些必要的分子。除军团菌外，还有许多 生长在宿主细胞内的病原体，使用常见的策略来建立感染，在 特别是复制液泡的形成和维持。因此，过氧化物体很可能是 对其他感染性细菌也很重要。拟议的研究将定义如何 过氧酶体使军团菌能够致病，同时避免被发现和 通过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.