Intracellular bacterial pathogens such as Legionella pneumophila induce a complex set of changes in the eukaryotic cells they infect. Some of these underlie the cell's defensive innate immune response, while other changes are subversions of the cell's own processes to benefit the bacterial replication cycle. The latter are induced by the secretion into the cell by L. pneumophila of diverse effector proteins. Understanding the range of cellular responses produced by these proteins, and how, remain major challenges in bacterial pathogenesis. Anecdotal reports indicate that mitochondria are affected by L. pneumophila infection but this has not been addressed clearly or quantitatively, and which aspects of mitochondrial behavior and function are modulated by L. pneumophila infection and effector protein secretion remain unknown. We seek to elucidate the full nature of the response of macrophage mitochondria to L. pneumophila infection, quantitatively and with good spatial and temporal resolution, and to identify the effectors that produce it. This study represents a new interdisciplinary collaboration between an investigator who studies the cell biology of mitochondria and another who is a specialist in L. pneumophila effector proteins. Together, our goal is to accrue detailed data that will allow us to frame and test informed and mechanistic hypotheses about the role or subversion of specific mitochondrial functions during infection of macrophages with L. pneumophila.
Our specific aims are: (1) to identify and characterize the responses of macrophage mitochondria to infection; (2) to determine which among the ~300 effector proteins are targeted to mitochondria, and which produce the mitochondrial phenotypes we observe.
Legionella pneumophila infection proceeds by commandeering the normal functions of our cells to serve the replication of the bacterium. We will investigate the ways in which infection alters the normal life cycle of mitochondria in target cells, how the bacterium produces these effects, and whether this response is a bacterial strategy or a cellular defense. This will provide a significant advance in our understanding of Legionella pathogenesis and will have an impact on preventative and therapeutic strategies.
| Gan, Ninghai; Nakayasu, Ernesto S; Hollenbeck, Peter J et al. (2018) Legionella pneumophila inhibits immune signalling via MavC-mediated transglutaminase-induced ubiquitination of UBE2N. Nat Microbiol : |
| Liu, Yao; Zhu, Wenhan; Tan, Yunhao et al. (2017) A Legionella Effector Disrupts Host Cytoskeletal Structure by Cleaving Actin. PLoS Pathog 13:e1006186 |
