Research Summary

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.

Research Funding

  • August 1, 2004 - July 31, 2024 - Microbial Pathogenesis and Host Defense , Principal Investigator . Sponsor: NIH, Sponsor Award ID: T32AI060537
  • July 1, 2020 - June 30, 2022 - Understanding the role of sensory adaptation in bacterial mechanochemical signaling pathways , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI154350
  • September 4, 2020 - August 31, 2021 - Inclusion membrane protein (Inc) modulation of the innate immune response to Chlamydia trachomatis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R56AI152526
  • August 1, 2017 - July 31, 2021 - Adapting to a changing environment: How surface contact induces virulence factor production in Pseudomonas aeruginosa , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI129547
  • December 1, 2015 - November 30, 2020 - Decoding the Chlamydia inclusion membrane protein-host protein interactome , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI122747
  • April 15, 2007 - August 31, 2018 - Novel approaches to identify host genes required for Chlamydia pathogenesis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI073770
  • May 1, 2005 - July 31, 2017 - New approaches to study Pseudomonas-host interactions , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R56AI065902
  • September 30, 1996 - June 30, 2016 - Comprehensive Biology: Exploiting the Yeast Genome , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR011823
  • September 17, 2013 - August 31, 2015 - High throughput proteomics to dissect Chlamydia-host cell interactions , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI105561
  • May 1, 2005 - May 31, 2015 - New approaches to study Pseudomonas-host interactions , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI065902
  • September 30, 2002 - August 31, 2014 - Mucosal Immune Barrier in Infection and Immunity , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01AI053194
  • June 1, 1998 - April 30, 2012 - Mechanism of Pseudomonas-mediated epithelial cell damage , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI042806
  • April 1, 2008 - March 31, 2012 - Proteomic approach to identify mediators of PI3K activation by P. aeruginosa , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R03TW008056
  • April 1, 2005 - March 31, 2007 - New approaches to studying host-chlamydia interactions , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI062768
  • February 1, 2000 - January 31, 2006 - BIOGENESIS OF THE CHLAMYDIA TRACHOMATIS VACUOLE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI044148
  • February 1, 1988 - January 31, 2002 - MOLECULAR BIOLOGY OF CHLAMYDIAL DEVELOPMENT , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI024436
  • June 1, 1996 - May 31, 2001 - MOLECULAR AND CELL BIOLOGY OF CHLAMYDIA TRACHOMATIS , Principal Investigator . Sponsor: NIH, Sponsor Award ID: K04AI001348
  • September 1, 1996 - October 31, 1997 - CELL BIOLOGY OF CHLAMYDIA, TRACHOMATIS , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI038271

Education

Yale University, New Haven, CT, B.S., 1976, Biochemistry
Stanford University, Palo Alto, CA, Ph.D., 1982, Biophysics
Stanford University, Palo Alto, CA, M.D., 1983, Medicine

Honors & Awards

  • 1976
    Phi Beta Kappa
  • 1976
    Sigma Xi
  • 1976
    Magna cum laude, Yale University
  • 1977
    Medical Scientist Training Program
  • 1988
    Lucille Markey Biomedical Scholar
  • 1994
    NIH Career Development Award
  • 1998
    American Lung Association Career Investigator
  • 2004
    President-Elect, Division B of American Society for Microbiology

Selected Publications

  1. Kühn MJ, Macmillan H, Talà L, Inclan Y, Patino R, Pierrat X, Al-Mayyah Z, Engel JN, Persat A. Two antagonistic response regulators control Pseudomonas aeruginosa polarization during mechanotaxis. EMBO J. 2023 04 03; 42(7):e112165.  View on PubMed
  2. Polvoy I, Seo Y, Parker M, Stewart M, Siddiqua K, Manacsa HS, Ravanfar V, Blecha J, Hope TA, Vanbrocklin H, Flavell RR, Barry J, Hansen E, Villanueva-Meyer JE, Engel J, Rosenberg OS, Wilson DM, Ohliger MA. Imaging joint infections using D-methyl-11C-methionine PET/MRI: initial experience in humans. Eur J Nucl Med Mol Imaging. 2022 09; 49(11):3761-3771.  View on PubMed
  3. Kühn MJ, Talà L, Inclan YF, Patino R, Pierrat X, Vos I, Al-Mayyah Z, Macmillan H, Negrete J, Engel JN, Persat A. Mechanotaxis directs Pseudomonas aeruginosa twitching motility. Proc Natl Acad Sci U S A. 2021 07 27; 118(30).  View on PubMed
  4. Peters JM, Koo BM, Patino R, Heussler GE, Hearne CC, Qu J, Inclan YF, Hawkins JS, Lu CHS, Silvis MR, Harden MM, Osadnik H, Peters JE, Engel JN, Dutton RJ, Grossman AD, Gross CA, Rosenberg OS. Enabling genetic analysis of diverse bacteria with Mobile-CRISPRi. Nat Microbiol. 2019 02; 4(2):244-250.  View on PubMed
  5. Kumagai K, Elwell CA, Ando S, Engel JN, Hanada K. Both the N- and C- terminal regions of the Chlamydial inclusion protein D (IncD) are required for interaction with the pleckstrin homology domain of the ceramide transport protein CERT. Biochem Biophys Res Commun. 2018 11 10; 505(4):1070-1076.  View on PubMed
  6. Elwell C, Engel J. Emerging Role of Retromer in Modulating Pathogen Growth. Trends Microbiol. 2018 09; 26(9):769-780.  View on PubMed
  7. Ruch TR, Engel JN. Targeting the Mucosal Barrier: How Pathogens Modulate the Cellular Polarity Network. Cold Spring Harb Perspect Biol. 2017 Jun 01; 9(6).  View on PubMed
  8. 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 03 02; 6.  View on PubMed
  9. Duncan MC, Herrera NG, Johnson KS, Engel JN, Auerbuch V. Bacterial internalization is required to trigger NIK-dependent NF-κB activation in response to the bacterial type three secretion system. PLoS One. 2017; 12(2):e0171406.  View on PubMed
  10. Ruch TR, Bryant DM, Mostov KE, Engel JN. Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity. Mol Biol Cell. 2017 01 15; 28(2):252-260.  View on PubMed
  11. 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 08; 101(4):590-605.  View on PubMed
  12. Elwell C, Mirrashidi K, Engel J. Chlamydia cell biology and pathogenesis. Nat Rev Microbiol. 2016 06; 14(6):385-400.  View on PubMed
  13. 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 08; 18(1):109-21.  View on PubMed
  14. Persat A, Inclan YF, Engel JN, Stone HA, Gitai Z. Type IV pili mechanochemically regulate virulence factors in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 2015 Jun 16; 112(24):7563-8.  View on PubMed
  15. 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.  View on PubMed
  16. 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.  View on PubMed
  17. Engel J, Matthay M. Cystic fibrosis epithelial cell and bacterial binding. Am J Physiol Lung Cell Mol Physiol. 2013 Dec; 305(11):L891.  View on PubMed
  18. 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.  View on PubMed
  19. Bastidas RJ, Elwell CA, Engel JN, Valdivia RH. Chlamydial intracellular survival strategies. Cold Spring Harb Perspect Med. 2013 May 01; 3(5):a010256.  View on PubMed
  20. Kim JH, Chan C, Elwell C, Singer MS, Dierks T, Lemjabbar-Alaoui H, Rosen SD, Engel JN. Endosulfatases SULF1 and SULF2 limit Chlamydia muridarum infection. Cell Microbiol. 2013 Sep; 15(9):1560-71.  View on PubMed

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