Deciphering the role of peroxisomes in bacterial pathogenesis

点击翻译按钮获取中文摘要

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.