Our laboratory focuses on the study of bacterial pathogenesis. We are interested in the molecular mechanisms by which bacterial pathogens manipulate host cellular processes to facilitate intracellular survival. Legionella pneumophila is an excellent model organism used to address these questions. This gram-negative bacterium is a parasite of fresh water protozoa, but can also infect human alveolar macrophages and cause a severe pneumonia, known as Legionnaires’ disease. To survive inside of host cells, L. pneumophila requires a specialized type-IV secretion system termed Dot/Icm. This secretion system is responsible for delivering bacterial effector proteins into host cells during infection. This activity is crucial for the ability of the bacterium to remodel the vacuole in which it resides, preventing delivery of the vacuole to lysosomes, and promoting recruitment of endoplasmic reticulum-derived vesicles to this vacuole to create a unique oraganelle in which the bacterium survives and replicates.
The intracellular lifecycle of L. pneumophila. Adapted from S. Ninio, C. R. Roy, Trends in Microbiology 15, 372 (2007).
Over the past number of years a large number of Dot/Icm effectors have been discovered. Some effectors have been implicated in the biogenesis of the L. pneumophila replication vacuole, however, the function of most L. pneumophila effectors remains unknown. It is also not clear how such a large repertoire of effector proteins is regulated spatially and temporally during infection. Previous work on the effector PieA suggests a novel mechanism for the spatial regulation of effectors inside host cells. PieA binds to the cytoplasmic face of the L. pneumophila vacuole by a mechanism that is dependent on the Dot/Icm system and involves protein-protein interaction. Moreover, binding of PieA to the L. pneumophila vacuole occurs only after this vacuole has been modified by the bacterium. In recent work we have identified L. pneumophila mutants that are defective in the ability to recruit PieA to the replication vacuole. These mutants are now being characterized to reveal new bacterial factors that are important for the remodeling of the host vacuole containing L. pneumophila into a specialized vacuole that supports bacterial survival and replication. Other projects in the lab focus on the study of effector protein activity, and are aimed at understand how these bacterial proteins function inside the host cell, and how they are spatially and temporally regulated during infection.
The effector PieA binds to the cytoplasmic face of host vacuoles containing L. pneumophila, in a mechanism dependent upon protein–protein interaction. Adapted from S. Ninio, J. Celli, C. R. Roy, PLoS Pathog 5, e1000278 (2009)
Selected publications:
"A Legionella pneumophila effector protein encoded in a region of genomic plasticity binds to Dot/Icm-modified vacuoles."
Ninio S, Celli J, and Roy CR.
PLoS Pathog., 5: e1000278, 2009.
"Effector proteins translocated by Legionella pneumophila: strength in numbers."
Ninio S and Roy CR.
Trends Microbiol., 15: 372-80, 2007.
"The Legionella IcmS-IcmW protein complex is important for Dot/Icm-mediated protein translocation."
Ninio S, Zuckman-Cholon DM, Cambronne ED, and Roy CR.
Molecular Microbiology. 55: 912-926, 2005.
"The membrane topology of EmrE – a small multidrug transporter from Escherichia coli."
Ninio S, Elbaz S, and Schuldiner S.
FEBS Lett., 563: 193-196, 2004.
"Characterization of an archaeal multidrug transporter with a unique amino acid composition."
Ninio S and Schuldiner S.
Journal of Biological Chemistry., 278: 12000-12005, 2003.
"Functional analysis of novel multidrug transporters from human pathogens."
Ninio S, Rotem D.and Schuldiner S
Journal of Biological Chemistry., 276: 48250-48256, 2001.
Precious things come in little packages.
Schuldiner S, Granot D, Steiner Mordoch S, Ninio S, Rotem D, Soskin M and Yerushalmi H.
Journal of Molecular Microbiology and Biotechnology, 2: 155-162, 2001.
Small is Mighty: EmrE, a multidrug transporter as an experimental paradigm.
Schuldiner S, Granot D, Steiner Mordoch S, Ninio S, Rotem D, Soskin M, Tate CG and Yerushalmi H.
News Physiol. Sci., 16: 130-134, 2001.
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