Joanne Engel, MD, PhD

Professor of Medicine
Medicine

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.

Publications: 

Mechanotaxis directs Pseudomonas aeruginosa twitching motility.

Proceedings of the National Academy of Sciences of the United States of America

Kühn MJ, Talà L, Inclan YF, Patino R, Pierrat X, Vos I, Al-Mayyah Z, Macmillan H, Negrete J, Engel JN, Persat A

Enabling genetic analysis of diverse bacteria with Mobile-CRISPRi.

Nature microbiology

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

Targeting the Mucosal Barrier: How Pathogens Modulate the Cellular Polarity Network.

Cold Spring Harbor perspectives in biology

Ruch TR, Engel JN

Chlamydia interfere with an interaction between the mannose-6-phosphate receptor and sorting nexins to counteract host restriction.

eLife

Elwell CA, Czudnochowski N, von Dollen J, Johnson JR, Nakagawa R, Mirrashidi K, Krogan NJ, Engel JN, Rosenberg OS

Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity.

Molecular biology of the cell

Ruch TR, Bryant DM, Mostov KE, Engel JN

A scaffold protein connects type IV pili with the Chp chemosensory system to mediate activation of virulence signaling in Pseudomonas aeruginosa.

Molecular microbiology

Inclan YF, Persat A, Greninger A, Von Dollen J, Johnson J, Krogan N, Gitai Z, Engel JN

Chlamydia cell biology and pathogenesis.

Nature reviews. Microbiology

Elwell C, Mirrashidi K, Engel J

Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection.

Cell host & microbe

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

Type IV pili mechanochemically regulate virulence factors in Pseudomonas aeruginosa.

Proceedings of the National Academy of Sciences of the United States of America

Persat A, Inclan YF, Engel JN, Stone HA, Gitai Z

The Pseudomonas aeruginosa type III translocon is required for biofilm formation at the epithelial barrier.

PLoS pathogens

Tran CS, Rangel SM, Almblad H, Kierbel A, Givskov M, Tolker-Nielsen T, Hauser AR, Engel JN

Host cell polarity proteins participate in innate immunity to Pseudomonas aeruginosa infection.

Cell host & microbe

Tran CS, Eran Y, Ruch TR, Bryant DM, Datta A, Brakeman P, Kierbel A, Wittmann T, Metzger RJ, Mostov KE, Engel JN

Sugar administration is an effective adjunctive therapy in the treatment of Pseudomonas aeruginosa pneumonia.

American journal of physiology. Lung cellular and molecular physiology

Bucior I, Abbott J, Song Y, Matthay MA, Engel JN

Chlamydial intracellular survival strategies.

Cold Spring Harbor perspectives in medicine

Bastidas RJ, Elwell CA, Engel JN, Valdivia RH

Endosulfatases SULF1 and SULF2 limit Chlamydia muridarum infection.

Cellular microbiology

Kim JH, Chan C, Elwell C, Singer MS, Dierks T, Lemjabbar-Alaoui H, Rosen SD, Engel JN

Lipid acquisition by intracellular Chlamydiae.

Cellular microbiology

Elwell CA, Engel JN

Chlamydia trachomatis co-opts the FGF2 signaling pathway to enhance infection.

PLoS pathogens

Kim JH, Jiang S, Elwell CA, Engel JN

Chlamydia trachomatis co-opts GBF1 and CERT to acquire host sphingomyelin for distinct roles during intracellular development.

PLoS pathogens

Elwell CA, Jiang S, Kim JH, Lee A, Wittmann T, Hanada K, Melancon P, Engel JN

Cell migration regulates the kinetics of cytokinesis.

Cell cycle (Georgetown, Tex.)

Wood S, Sivaramakrishnan G, Engel J, Shafikhani SH

FimL regulates cAMP synthesis in Pseudomonas aeruginosa.

PloS one

Inclan YF, Huseby MJ, Engel JN

Role of Pseudomonas aeruginosa type III effectors in disease.

Current opinion in microbiology

Engel J, Balachandran P

Focal adhesion components are essential for mammalian cell cytokinesis.

Cell cycle (Georgetown, Tex.)

Shafikhani SH, Mostov K, Engel J

Roles of type IV pili, flagellum-mediated motility and extracellular DNA in the formation of mature multicellular structures in Pseudomonas aeruginosa biofilms.

Environmental microbiology

Barken KB, Pamp SJ, Yang L, Gjermansen M, Bertrand JJ, Klausen M, Givskov M, Whitchurch CB, Engel JN, Tolker-Nielsen T

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 immunology and medical microbiology

Brandt S, Shafikhani S, Balachandran P, Jin S, Hartig R, König W, Engel J, Backert S

Pseudomonas aeruginosa exploits a PIP3-dependent pathway to transform apical into basolateral membrane.

The Journal of cell biology

Kierbel A, Gassama-Diagne A, Rocha C, Radoshevich L, Olson J, Mostov K, Engel J

Copper and nitric oxide meet in the plasma.

Nature chemical biology

Samuel TK, Gitlin JD

An essential, putative MEK kinase of Leishmania major.

Molecular and biochemical parasitology

Agron PG, Reed SL, Engel JN

Pseudomonas aeruginosa fimL regulates multiple virulence functions by intersecting with Vfr-modulated pathways.

Molecular microbiology

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

Lipid raft-mediated entry is not required for Chlamydia trachomatis infection of cultured epithelial cells.

Infection and immunity

Gabel BR, Elwell C, van Ijzendoorn SC, Engel JN

A mycobacterial virulence gene cluster extending RD1 is required for cytolysis, bacterial spreading and ESAT-6 secretion.

Molecular microbiology

Gao LY, Guo S, McLaughlin B, Morisaki H, Engel JN, Brown EJ

Tarp and Arp: How Chlamydia induces its own entry.

Proceedings of the National Academy of Sciences of the United States of America

Engel J

Characterization of a complex chemosensory signal transduction system which controls twitching motility in Pseudomonas aeruginosa.

Molecular microbiology

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

The ADP ribosyltransferase domain of Pseudomonas aeruginosa ExoT contributes to its biological activities.

Infection and immunity

Garrity-Ryan L, Shafikhani S, Balachandran P, Nguyen L, Oza J, Jakobsen T, Sargent J, Fang X, Cordwell S, Matthay MA, Engel JN

Epithelial cell polarity alters Rho-GTPase responses to Pseudomonas aeruginosa.

Molecular biology of the cell

Kazmierczak BI, Mostov K, Engel JN

Pseudomonas aeruginosa ExoT inhibits in vitro lung epithelial wound repair.

Cellular microbiology

Geiser TK, Kazmierczak BI, Garrity-Ryan LK, Matthay MA, Engel JN

Rho GTPase activity modulates Pseudomonas aeruginosa internalization by epithelial cells.

Cellular microbiology

Kazmierczak BI, Jou TS, Mostov K, Engel JN

Interaction of bacterial pathogens with polarized epithelium.

Annual review of microbiology

Kazmierczak BI, Mostov K, Engel JN

Host cell-derived sphingolipids are required for the intracellular growth of Chlamydia trachomatis.

Cellular microbiology

van Ooij C, Kalman L, Nishijima M, Hanada K, Mostov K, Engel JN

Eukaryotic cell uptake of heparin-coated microspheres: a model of host cell invasion by Chlamydia trachomatis.

Infection and immunity

Stephens RS, Fawaz FS, Kennedy KA, Koshiyama K, Nichols B, van Ooij C, Engel JN

Defects in type III secretion correlate with internalization of Pseudomonas aeruginosa by epithelial cells.

Infection and immunity

Hauser AR, Fleiszig S, Kang PJ, Mostov K, Engel JN

Identification of Pseudomonas aeruginosa genes required for epithelial cell injury.

Molecular microbiology

Kang PJ, Hauser AR, Apodaca G, Fleiszig SM, Wiener-Kronish J, Mostov K, Engel JN

Characterization of Pseudomonas aeruginosa-induced MDCK cell injury: glycosylation-defective host cells are resistant to bacterial killing.

Infection and immunity

Apodaca G, Bomsel M, Lindstedt R, Engel J, Frank D, Mostov KE, Wiener-Kronish J

Stage-specific regulation of protein phosphorylation in Leishmania major.

Molecular and biochemical parasitology

Dell KR, Engel JN

Cloning and characterization of the RNA polymerase alpha-subunit operon of Chlamydia trachomatis.

Journal of bacteriology

Tan M, Klein R, Grant R, Ganem D, Engel J

A developmentally regulated chlamydial gene with apparent homology to eukaryotic histone H1.

Proceedings of the National Academy of Sciences of the United States of America

Perara E, Ganem D, Engel JN

Heat shock response of murine Chlamydia trachomatis.

Journal of bacteriology

Engel JN, Pollack J, Perara E, Ganem D

Phenytoin hypersensitivity: a case of severe acute rhabdomyolysis.

The American journal of medicine

Engel JN, Mellul VG, Goodman DB

Phenytoin hypersensitivity: a case of severe acute rhabdomyolysis

American Journal of Medicine

Engel, JN, Mellul, VG, Goodman, DBP

Evolutionary conservation in the untranslated regions of actin mRNA's

Nucleic acids research

Ponte, P, Ng, SY, Engel, JN, Kedes, LH

Isolation and characterization of human actin genes. Ph.D. Dissertation, Stanford University

Isolation and characterization of human actin genes. Ph.D. Dissertation, Stanford University

Engel, JN

Molecular genetics of human myogenesis

Experimental Biology and Medicine

Kedes, LH, Blau, H, Gunning, P, Ponte, P, Chiu, C-P, Bain, W, Engel, JN, Guttman, S

Human cytoplasmic actin proteins are encoded by a multigene family

Molecular and cellular biology

Engel, JN, Gunning, P, Kedes, LH

Isolation and characterization of human actin genes.

Proceedings of the National Academy of Sciences of the United States of America

Engel JN, Gunning PW, Kedes L

Isolation and characterization of human actin genes

Proceedings National Academy of Sciences

Engel, JN, Gunning, P, Kedes, LH