期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：6
页码：1821-1826
DOI：10.1073/pnas.1424954112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificancePathogens express virulence factors to support their growth and reproduction while hosts activate various immune processes to promote pathogen clearance and minimize damage. In this study, we establish a new role for pyoverdin, an iron-binding siderophore produced by the bacterium Pseudomonas aeruginosa. In addition to promoting growth by acquiring iron, pyoverdin serves as a secreted bacterial toxin that disrupts mitochondria and iron homeostasis in Caenorhabditis elegans. We show that exposure to pyoverdin triggers mitochondrial damage and subsequent mitophagy (lysosomal degradation of damaged mitochondria). Importantly, mitophagy confers a protective effect against exposure to either pyoverdin or to a synthetic iron chelator, demonstrating a function for mitophagy in innate immunity. Finally, we show that iron chelation causes mitophagy in mammalian cells. In the arms race of bacterial pathogenesis, bacteria produce an array of toxins and virulence factors that disrupt core host processes. Hosts mitigate the ensuing damage by responding with immune countermeasures. The iron-binding siderophore pyoverdin is a key virulence mediator of the human pathogen Pseudomonas aeruginosa, but its pathogenic mechanism has not been established. Here we demonstrate that pyoverdin enters Caenorhabditis elegans and that it is sufficient to mediate host killing. Moreover, we show that iron chelation disrupts mitochondrial homeostasis and triggers mitophagy both in C. elegans and mammalian cells. Finally, we show that mitophagy provides protection both against the extracellular pathogen P. aeruginosa and to treatment with a xenobiotic chelator, phenanthroline, in C. elegans. Although autophagic machinery has been shown to target intracellular bacteria for degradation (a process known as xenophagy), our report establishes a role for authentic mitochondrial autophagy in the innate immune defense against P. aeruginosa.
