Faculty ProfilesJoanne Engel, MD, PhD
513 Parnassus Ave
San Francisco, CA 94143
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 to the study of P. aeruginosa-host interactions is (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 upon binding to the apical surface of polarized epithelial cells, P. aeruginosa forms biofilm-like structures that are able to transform apical membrane into basolateral membrane by exploiting the phosphatidyl inositol kinase pathway to form membrane protrusions that are associated with a spatial and temporal activation of the innate immune response. Our current studies focus on the dissection of the Chp/Vfr/ regulatory pathway that regulates diverse virulence factor circuits in P. aeruginosa in determining the bacterial and host determinants involved in the formation of biofilms and spatially localized activation of the innate immune response at the apical surface of tissues. In our studies on the pathogenesis of chlamydial infections, we have focused on 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.
Education and Training
|Location||Degree or Training||Specialty||Date|
|University of California, San Francisco||Post-Doc Fellow/Scholar||Medicine (Laboratory Medicine)||1989|
|Stanford University||M.D.||School of Medicine||1983|
|University of California, San Francisco||Residency|
Related Web Sites
|Project Title||Project Number||Fiscal Year|
|Comprehensive Biology: Exploiting the Yeast Genome||P41RR011823||2016|
Elwell CA, Czudnochowski N, von Dollen J, Johnson JR, Nakagawa R, Mirrashidi K, Krogan NJ, Engel JN, Rosenberg OS. Chlamydia interfere with an interaction between the mannose-6-phosphate receptor and sorting nexins to counteract host restriction. Elife. 2017 Mar 02; 6.
Inclan YF, Persat A, Greninger A, Von Dollen J, Johnson J, Krogan N, Gitai Z, Engel JN. A scaffold protein connects type IV pili with the Chp chemosensory system to mediate activation of virulence signaling in Pseudomonas aeruginosa. Mol Microbiol. 2016 May 3.
Mirrashidi KM, Elwell CA, Verschueren E, Johnson JR, Frando A, Von Dollen J, Rosenberg O, Gulbahce N, Jang G, Johnson T, Jäger S, Gopalakrishnan AM, Sherry J, Dunn JD, Olive A, Penn B, Shales M, Cox JS, Starnbach MN, Derre I, Valdivia R, Krogan NJ, Engel J. Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection. Cell Host Microbe. 2015 Jul 8; 18(1):109-21.
Tran CS, Rangel SM, Almblad H, Kierbel A, Givskov M, Tolker-Nielsen T, Hauser AR, Engel JN. The Pseudomonas aeruginosa type III translocon is required for biofilm formation at the epithelial barrier. PLoS Pathog. 2014 Nov; 10(11):e1004479.
Tran CS, Eran Y, Ruch TR, Bryant DM, Datta A, Brakeman P, Kierbel A, Wittmann T, Metzger RJ, Mostov KE, Engel JN. Host cell polarity proteins participate in innate immunity to Pseudomonas aeruginosa infection. Cell Host Microbe. 2014 May 14; 15(5):636-43.
Bucior I, Abbott J, Song Y, Matthay MA, Engel JN. Sugar administration is an effective adjunctive therapy in the treatment of Pseudomonas aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol. 2013 Sep; 305(5):L352-63.
Bucior I, Pielage JF, Engel JN. Pseudomonas aeruginosa pili and flagella mediate distinct binding and signaling events at the apical and basolateral surface of airway epithelium. PLoS Pathog. 2012; 8(4):e1002616.
Elwell CA, Jiang S, Kim JH, Lee A, Wittmann T, Hanada K, Melancon P, Engel JN. Chlamydia trachomatis co-opts GBF1 and CERT to acquire host sphingomyelin for distinct roles during intracellular development. PLoS Pathog. 2011 Sep; 7(9):e1002198.
Bucior I, Mostov K, Engel JN. Pseudomonas aeruginosa-mediated damage requires distinct receptors at the apical and basolateral surfaces of the polarized epithelium. Infect Immun. 2010 Mar; 78(3):939-53.
Barken KB, Pamp SJ, Yang L, Gjermansen M, Bertrand JJ, Klausen M, Givskov M, Whitchurch CB, Engel JN, Tolker-Nielsen T. Roles of type IV pili, flagellum-mediated motility and extracellular DNA in the formation of mature multicellular structures in Pseudomonas aeruginosa biofilms. Environ Microbiol. 2008 Sep; 10(9):2331-43.
Shafikhani SH, Morales C, Engel J. The Pseudomonas aeruginosa type III secreted toxin ExoT is necessary and sufficient to induce apoptosis in epithelial cells. Cell Microbiol. 2008 Apr; 10(4):994-1007.
Brandt S, Shafikhani S, Balachandran P, Jin S, Hartig R, König W, Engel J, Backert S. Use of a novel coinfection system reveals a role for Rac1, H-Ras, and CrkII phosphorylation in Helicobacter pylori-induced host cell actin cytoskeletal rearrangements. FEMS Immunol Med Microbiol. 2007 Jul; 50(2):190-205.
Kierbel A, Gassama-Diagne A, Rocha C, Radoshevich L, Olson J, Mostov K, Engel J. Pseudomonas aeruginosa exploits a PIP3-dependent pathway to transform apical into basolateral membrane. J Cell Biol. 2007 Apr 9; 177(1):21-7.
Kierbel A, Gassama-Diagne A, Mostov K, Engel JN. The phosphoinositol-3-kinase-protein kinase B/Akt pathway is critical for Pseudomonas aeruginosa strain PAK internalization. Mol Biol Cell. 2005 May; 16(5):2577-85.
Whitchurch CB, Beatson SA, Comolli JC, Jakobsen T, Sargent JL, Bertrand JJ, West J, Klausen M, Waite LL, Kang PJ, Tolker-Nielsen T, Mattick JS, Engel JN. Pseudomonas aeruginosa fimL regulates multiple virulence functions by intersecting with Vfr-modulated pathways. Mol Microbiol. 2005 Mar; 55(5):1357-78.
Gao LY, Guo S, McLaughlin B, Morisaki H, Engel JN, Brown EJ. A mycobacterial virulence gene cluster extending RD1 is required for cytolysis, bacterial spreading and ESAT-6 secretion. Mol Microbiol. 2004 Sep; 53(6):1677-93.
Whitchurch CB, Leech AJ, Young MD, Kennedy D, Sargent JL, Bertrand JJ, Semmler AB, Mellick AS, Martin PR, Alm RA, Hobbs M, Beatson SA, Huang B, Nguyen L, Commolli JC, Engel JN, Darzins A, Mattick JS. Characterization of a complex chemosensory signal transduction system which controls twitching motility in Pseudomonas aeruginosa. Mol Microbiol. 2004 May; 52(3):873-93.
Garrity-Ryan L, Shafikhani S, Balachandran P, Nguyen L, Oza J, Jakobsen T, Sargent J, Fang X, Cordwell S, Matthay MA, Engel JN. The ADP ribosyltransferase domain of Pseudomonas aeruginosa ExoT contributes to its biological activities. Infect Immun. 2004 Jan; 72(1):546-58.
McMorran B, Town L, Costelloe E, Palmer J, Engel J, Hume D, Wainwright B. Effector ExoU from the type III secretion system is an important modulator of gene expression in lung epithelial cells in response to Pseudomonas aeruginosa infection. Infect Immun. 2003 Oct; 71(10):6035-44.
Hauser AR, Cobb E, Bodi M, Mariscal D, Vallés J, Engel JN, Rello J. Type III protein secretion is associated with poor clinical outcomes in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Crit Care Med. 2002 Mar; 30(3):521-8.
Garrity-Ryan L, Kazmierczak B, Kowal R, Comolli J, Hauser A, Engel JN. The arginine finger domain of ExoT contributes to actin cytoskeleton disruption and inhibition of internalization of Pseudomonas aeruginosa by epithelial cells and macrophages. Infect Immun. 2000 Dec; 68(12):7100-13.
Stephens RS, Fawaz FS, Kennedy KA, Koshiyama K, Nichols B, van Ooij C, Engel JN. Eukaryotic cell uptake of heparin-coated microspheres: a model of host cell invasion by Chlamydia trachomatis. Infect Immun. 2000 Mar; 68(3):1080-5.
Comolli JC, Hauser AR, Waite L, Whitchurch CB, Mattick JS, Engel JN. Pseudomonas aeruginosa gene products PilT and PilU are required for cytotoxicity in vitro and virulence in a mouse model of acute pneumonia. Infect Immun. 1999 Jul; 67(7):3625-30.
Comolli JC, Waite LL, Mostov KE, Engel JN. Pili binding to asialo-GM1 on epithelial cells can mediate cytotoxicity or bacterial internalization by Pseudomonas aeruginosa. Infect Immun. 1999 Jul; 67(7):3207-14.
Van Ooij C, Homola E, Kincaid E, Engel J. Fusion of Chlamydia trachomatis-containing inclusions is inhibited at low temperatures and requires bacterial protein synthesis. Infect Immun. 1998 Nov; 66(11):5364-71.
Fawaz FS, van Ooij C, Homola E, Mutka SC, Engel JN. Infection with Chlamydia trachomatis alters the tyrosine phosphorylation and/or localization of several host cell proteins including cortactin. Infect Immun. 1997 Dec; 65(12):5301-8.
Kang PJ, Hauser AR, Apodaca G, Fleiszig SM, Wiener-Kronish J, Mostov K, Engel JN. Identification of Pseudomonas aeruginosa genes required for epithelial cell injury. Mol Microbiol. 1997 Jun; 24(6):1249-62.
Apodaca G, Bomsel M, Lindstedt R, Engel J, Frank D, Mostov KE, Wiener-Kronish J. Characterization of Pseudomonas aeruginosa-induced MDCK cell injury: glycosylation-defective host cells are resistant to bacterial killing. Infect Immun. 1995 Apr; 63(4):1541-51.
Engel JN, Pollack J, Malik F, Ganem D. Cloning and characterization of RNA polymerase core subunits of Chlamydia trachomatis by using the polymerase chain reaction. J Bacteriol. 1990 Oct; 172(10):5732-41.
Engel JN, Ganem D. A polymerase chain reaction-based approach to cloning sigma factors from eubacteria and its application to the isolation of a sigma-70 homolog from Chlamydia trachomatis. J Bacteriol. 1990 May; 172(5):2447-55.
Sardinia LM, Engel JN, Ganem D. Chlamydial gene encoding a 70-kilodalton antigen in Escherichia coli: analysis of expression signals and identification of the gene product. J Bacteriol. 1989 Jan; 171(1):335-41.
Engel, JN, Mellul, VG, Goodman, DBP. Phenytoin hypersensitivity: a case of severe acute rhabdomyolysis. American Journal of Medicine. 1986; 81:928-930.
Ponte, P, Ng, SY, Engel, JN, Kedes, LH. Evolutionary conservation in the untranslated regions of actin mRNA's. Nucleic Acids Research. 1984; 12:1687-1696.
Kedes, LH, Blau, H, Gunning, P, Ponte, P, Chiu, C-P, Bain, W, Engel, JN, Guttman, S. Molecular genetics of human myogenesis. Experimental Biology and Medicine. 1983; 9:202-212.
Engel, JN. Isolation and characterization of human actin genes. Ph.D. Dissertation, Stanford University. 1983.
Gunning, P, Ponte, P, Okayama, H, Engel, JN, Kedes, L. Isolation and characterization of full-length cDNA clones for human a-, b-, and c- actin mRNA's: skeletal but not cytoplasmic actins have an amino terminal cysteine that is subsequently removed. Molecular and Cellular Biology. 1983; 3:787-795.
Engel, JN, Gunning, P, Kedes, LH. Human cytoplasmic actin proteins are encoded by a multigene family. Molecular and Cellular Biology. 1982; 2:674-684.
Engel, JN, Gunning, P, Kedes, LH. Isolation and characterization of human actin genes. Proceedings National Academy of Sciences. 1981; 78:4674-4678.
Martin JE, Engel JN, Klein DC. Inhibition of the in vitro pituitary response to luteinizing hormone-releasing hormone by melatonin, serotonin, and 5-methoxytryptamine. Endocrinology. 1977 Mar; 100(3):675-80.
Martin, JE, Engel, JN, Klein, DC. Inhibition of the in vitro pituitary response to luteinizing hormone releasing hormone by melatonin, serotonin, and 5-methoxytryptamine. Endocrinology. 1977; 100:675-680.