Legionella pneumophila is the causative agent of a severe pneumonia called Legionnaires'disease. The ability of Legionella to replicate inside of phagocytic cells is central to host pathogenesis and requires a specialized secretion system called Dot/Icm. The focus of this project has been to determine how the Dot/Icm system enables Legionella to create an intracellular vacuole that supports replication. Towards this end, we have demonstrated that this process involves the subversion of host vesicles derived from the endoplasmic reticulum, which are used by Legionella to remodel the plasma membrane-derived organelle it occupies initially into a vacuole that resembles the endoplasmic reticulum. Proteins delivered into host cells by the Dot/Icm system promote this membrane transport pathway. Over the past funding period we have identified multiple bacterial proteins that target the host membrane transport regulator Rab1. To understand how these proteins control membrane transport and promote biogenesis of a vacuole that permits Legionella intracellular growth, we will investigate the function of these proteins during infection of host cells by Legionella. Specifically, we will determine how the biochemical activities of these proteins are regulated spatially and temporally during infection to coordinate the cycling of Rab1 on vacuoles containing Legionella, determine how Rab1 activation on the vacuole containing Legionella can promote the recruitment and fusion of endoplasmic reticulum-derived vesicles, and determine the role host proteins that regulate phosphatidylinositol 4-phosphate play in vacuole maturation.
Intracellular pathogens represent a serious threat to human health, and to devise strategies to combat infections by these microbes a more detailed understanding of how they modulate host cell function is needed. Thus, this project is focused on determining the molecular mechanisms that allow the intracellular pathogen Legionella pneumophila to regulate vesicular transport in eukaryotic cells using novel bacterial proteins that manipulate the function of host proteins to enhance replication and survival.
|Chetrit, David; Hu, Bo; Christie, Peter J et al. (2018) A unique cytoplasmic ATPase complex defines the Legionella pneumophila type IV secretion channel. Nat Microbiol 3:678-686|
|Meir, Amit; Chetrit, David; Liu, Luying et al. (2018) Legionella DotM structure reveals a role in effector recruiting to the Type 4B secretion system. Nat Commun 9:507|
|Shames, Stephanie R; Liu, Luying; Havey, James C et al. (2017) Multiple Legionella pneumophila effector virulence phenotypes revealed through high-throughput analysis of targeted mutant libraries. Proc Natl Acad Sci U S A 114:E10446-E10454|
|Tørring, Thomas; Shames, Stephanie R; Cho, Wooyoung et al. (2017) Acyl Histidines: New N-Acyl Amides from Legionella pneumophila. Chembiochem 18:638-646|
|Guzmán-Herrador, Dolores L; Steiner, Samuel; Alperi, Anabel et al. (2017) DNA Delivery and Genomic Integration into Mammalian Target Cells through Type IV A and B Secretion Systems of Human Pathogens. Front Microbiol 8:1503|
|Kohler, Lara J; Roy, Craig R (2017) Autophagic targeting and avoidance in intracellular bacterial infections. Curr Opin Microbiol 35:36-41|
|Horenkamp, Florian A; Kauffman, Karlina J; Kohler, Lara J et al. (2015) The Legionella Anti-autophagy Effector RavZ Targets the Autophagosome via PI3P- and Curvature-Sensing Motifs. Dev Cell 34:569-76|
|Havey, James C; Roy, Craig R (2015) Toxicity and SidJ-Mediated Suppression of Toxicity Require Distinct Regions in the SidE Family of Legionella pneumophila Effectors. Infect Immun 83:3506-14|
|Hubber, Andree; Arasaki, Kohei; Nakatsu, Fubito et al. (2014) The machinery at endoplasmic reticulum-plasma membrane contact sites contributes to spatial regulation of multiple Legionella effector proteins. PLoS Pathog 10:e1004222|
|Horenkamp, Florian A; Mukherjee, Shaeri; Alix, Eric et al. (2014) Legionella pneumophila subversion of host vesicular transport by SidC effector proteins. Traffic 15:488-99|
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