My lab is interested in the complex interplay between bacterial pathogens and host cells. In particular, we study two important human pathogens, Chlamydia trachomatis and Pseudomonas aeruginosa. Our strengths include using multidisciplinary approaches to these studies—allowing the pathogen to be our tutor. We have utilized bacterial genetics and genetic screens, molecular biology, cellular microbiology, host cell biology with advanced immunofluorescence microscopy, genome-wide RNAi screens, bioinformatics, and proteomics to rigorously understand the mechanisms by which they subvert host cell functions to cause disease. Seminal contributions that our group has made include (i) the discovery of the P. aeruginosa type III secretion system and one of the secreted effectors ExoU and the demonstration that the P. aeruginosa type III secretion system is important for virulence in cell-culture, mouse, and human infections (ii) demonstrating that the type III secreted toxin ExoT inhibits wound repair through redundant pathways (iii) elucidation of the pathway by which P. aeruginosa can be internalized by non-phagocytic cells and how the type III secretion system-encoded effectors modulate entry (iv) characterization of novel genes involved in type IV pilin biogenesis and in the regulation of diverse virulence pathways (v) the first identification of a host cell ubiquitin ligase (cbl-b) that specifically targets the degradation of a type III secreted factor (vii) development of 2D and 3D cell-culture based systems to dissect the interaction of pathogens with the apical versus basolateral surface of polarized epithelial cells (vi) discovery that P. aeruginosa is able to transform apical membrane into basolateral membrane by exploiting the phosphatidyl inositol kinase pathway (viii) application of host cell biology and genome-wide RNA-based screens to understanding how C. trachomatis modulates host cell signaling systems to bind, enter, and establish a replicative niche. We have carried out a genome wide RNAi screen in a simple genetic host and have identified new host molecules that are involved in binding, entry, and establishment of a unique intracellular niche. We have discovered a potential role for host growth factors in binding and entry and elucidated a novel pathway by which this organism acquires sphingolipids from the host. We have complemented these studies with state of the art confocal microscopy to begin to elucidate the bacterial and host determinants and mechanism of vacuole fusion. We are currently carrying out high throughput proteomics to dissect the function of the approximately 150 proteins that Chlamydia inject into the host cell to create a unique replicative niche and to escape the innate immune response.
Eran, Y. and Engel, J. N. Subversion of mucosal barrier polarity by Pseudomonas aeruginosa, Frontiers in Cellular and Infection Microbiology, 2011, in press.
Elwell C.A, Kierbel A., and Engel, J.N. 2011. Specifies-specific interactions of Src family tyrosine kinases regulate Chlamydia intracellular growth and trafficking. mBio 2: e00082-11. doi:10.1128/mBio.00082-11, in press.
Inclan, Y.F., Huseby, M.J., and Engel, J.N, FimL Regulates cAMP Synthesis in Pseudomonas aeruginosa. PLoS One. 2011 Jan 11;6(1):e15867.PMID: 21264306
Bucior I, Mostov K, Engel JN. Pseudomonas aeruginosa-mediated damage requires distinct receptors at the apical and basolateral surfaces of polarized epithelium. Infect Immun. 78:339-343, 2010. PMID: 20008530.
Bertrand JJ, West JT, Engel JN. Genetic analysis of the regulation of type IV pilus function by the Chp chemosensory system of Pseudomonas aeruginosa. J Bacteriol. 192:994-1010, 2010. PMID: 20008072.
Endoh, T., and Engel, J.N., CbpA, a novel polarly localized protein in Pseudomonas aeruginosa, J. Bacteriology, 123:193-205, 2009. PMID: 20008072.
Balachandran, P and Engel, J.. Role of Pseudomonas aeruginosa type III effectors in disease, Current Opinion in Microbiology 12:61-66, 2009. PMID: 19168385.
Shafikhani, S. H. Mostov, K. and Engel, J.N., Crk and Paxillin, components of focal adhesions, are essential for mammalian cell cytokinesis, Cell Cycle, 7:2868-2876, 2008. PMID: 18787414.
Pielage, J., Powell, K. R., Kalman, D., and Engel, J.N., RNAi screen reveals an Abl kinase-dependent host cell pathway involved in Pseudomonas aeruginosa internalization, Plos Pathogens, 4: 10000031, 2008. PMID: 18369477.
Elwell, C., Ceesay, A., Kim, J.H., Kalman, D., and Engel, J.N., RNA Interference Screen Identifies Abl Kinase and PDGFR Signaling pathways in Chlamydia trachomatis Entry, Plos Pathogens 4: e1000021, 2008. PMID: 18369471.
Shafikhani, S., H. Morales, C., and Engel, J.N., The Pseudomonas aeruginosa type III secreted toxin ExoT is necessary and sufficient to induce apoptosis in epithelial cells, Cellular Microbiology, 10:994-1007, 2008. PMID: 18053004.
Kierbel, A., Gassama-Digne, A., Rocha, C., Radoshevich, L., Olson, J., Mostov, K., and Engel, J.N., Pseudomonas aeruginosa exploits a PIP3-dependent mechanism to transform apical into basolateral membrane, Journal of Cell Biology, 177:21-27, 2007. PMID: 17403925. Highlighted in the issue. Cited as an "editor's choice" article in Science April, 2007. Highlighted in Nature Reviews Microbiology.
Balachandran, P., Dragone, Garrity-Ryan, L., Lemus, A., L, Weiss, A., and Engel, J.N., Pseudomonas aeruginosa Exotoxin T-mediated virulence is limited by the ubiquitin ligase Cbl-b, Journal of Clinical Investigation, 117:419-427, 2007. PMID: 17235393. Highlighted in the issue. Cited by faculty of 1000 biology.
Engel, J.N., The Molecular Mechanisms of Pseudomonas aeruginosa entry, Pseudomonas book series, 2007.
Shafikhani, S. and Engel, J.N., Pseudomonas aeruginosa type III secreted toxin ExoT inhibits host cell division by targeting cytokinesis at multiple steps, Proc Nat Acad Sci 103:15605-15610, 2006. PMID: 17030800. Cited as an "editor's choice" article in Science Oct 20, 2006 and highlighted in nature reviews microbiology.
Gassama-Digne, A., Yu, W., ter Beest, M., Martin-Ernandez, F., Kierbel, A., Engel, J.N., and Mostov, K.. Phosphatidylinositol 3,4,5-trisphosphate is necessary and sufficient for formation of the basolateral plasma membrane, Nature Cell Biology, 9:963-970, 2006. PMID: 16921364. Cited as an "editor's choice" article in Science STKE (Signal Transduction Knowledge Environment) Sept 12, 2006.
Kierbel, A., Gassama, A., Mostov, K., and Engel, J.N., The Phosphoinositol-3-kinase-Protein kinase B/Akt pathway is critical for Pseudomonas aeruginosa strain PAK internalization, Molecular Biology of the Cell, 16:2577, 2005. PMID: 15772151.
Elwell, C. and Engel, J.N., Chlamydia trachomatis infection of Drosophila melanogaster S2 cells mimics early steps in mammalian infection, Cellular Microbiology, 7:725, 2005. PMID: 15839901.
Whitchurch, C., Beatson, S., Comolli, J., Jakobsen, T., Sargent, J., Bertrand, J. , West, J., Klausen, M., Waite, L., Kang, P. J., Tolker-Nielson, T., Mattick, J., and Engel, J.N., FimL, a novel Pseudomonas aeruginosa gene product involved in twitching motility, Molecular Microbiology, 55:1357, 2005. PMID: 15720546.