Bacteriology; Genetics, Microbial; Microbiology
Our laboratory studies the pathogenesis of two intestinal pathogens, Salmonella enterica and Campylobacter jejuni. Combined, these two pathogens account for the majority of cases of infectious diarrhea world-wide leading to an estimated 2,000,000 deaths. We take a multidisciplinary approach in our studies involving bacterial genetics, biochemistry, cell biology, immunology as well as structural biology. As a result, we are beginning to define not only the molecular details of the host pathogen interactions but also the atomic interphase between these pathogens and the host.
Extensive Research Description
Microbial pathogens have evolved
unique ways to interact with their hosts. In many instances the terms of this interaction reflect the
co-evolutionary balance that the host and pathogen must reach in order to secure
their survival. It is therefore
not surprising that bacterial pathogens have evolved a large array of virulence
factors well suited to interfere with or stimulate a variety of host-cell
responses in order to invade, survive and replicate within their hosts. The identification and characterization
of these virulence factors is proving to be a fruitful area of research in more
ways than expected.
The understanding of how pathogens interact with their hosts is not only providing the basis for the development of novel therapeutic approaches but also a number of very sophisticated tools for probing basic aspects of cellular physiology and immunology. Our laboratory studies the pathogenesis of two intestinal pathogens, Salmonella enterica and Campylobacter jejuni. Combined, these two pathogens account for the vast majority of cases of infectious diarrhea world-wide leading to an estimated 2,000,000 deads. We are interested in characterizing the bacterial determinants involved in these interactions as well as the cell biology and immunobiology of this process.
We take a multidisciplinary approach in our studies involving bacterial genetics, biochemistry, cell biology, immunology as well as structural biology. As a result, we are beginning to define not only the molecular details of the host pathogen interactions but also the atomic interphase between these pathogens and the host. Our laboratory has also an interest in vaccine development that stems from our discovery of a specialized organelle in Salmonella enterica (the “type III secretion system”) that mediates the transfer of bacterial proteins into host cells. We have harnessed this system for the delivery of heterologous proteins as a means to delivery antigens to the Class I and Class II antigen presenting pathways by avirulent strains of Salmonella.
Specific areas of interest include:
- The study of type III secretion, a specialized bacterial organelle whose function is to delivery bacterial proteins into eukaryotic host cells. We are interested in understanding the mechanism of action of this multi-protein machine, as well as to understand the activities of the proteins delivered by this machine. We carried out these studies in Salmonella enterica but it is expected that knowledge gained from these studies may help understand the pathogenesis of many other bacteria since this system is conserved and widespread among several important pathogens.
- The harnessing of the protein-delivery capability of the type III secretion machine for the development of therapeutic approaches, including vaccines.
- The development of strategies that target the activities of type III secretion systems with the ultimate goal of developing new therapeutics to combat diseases caused by pathogens that encode these protein-delivery machines.
- The study the mechanism of pathogenesis of Salmonella typhi, which can only infect humans causing typhoid fever, a life-threatening disease that causes more than 500,000 deaths world-wide. We focus our efforts on the study of "typhoid toxin", a toxin exclusively produced by Salmonella typhi that we recently identified.
- The study of the mechanisms by which Campylobacter jejuni enters and survives within host cells. In particular, we are interested in understanding how this bacterium harnesses host-cell machinery to gain access to the cell, deviating from standard endocytic pathways and thus avoiding delivery to lysosomes.
- The investigation of the in vivo metabolism of C. jejuni. We are specifically interested in identifying its carbon sources and respiration substrates during infection.
Chaperone release and unfolding of substrates in type III secretion.
Akeda Y, Galan JE. (2005). Chaperone release and unfolding of substrates in type III secretion. Nature 437: 911-915.
Assembly of the inner rod determines needle length in the type III secretion injectisome
Marlovitz, T.C., Kubori, T., Lara-Tejero, M., Thomas, D.R., Unger, V.M., and Galán, J.E. (2006). Assembly of the inner rod determines needle length in the type III secretion injectisome. Nature 441(7093):637-40.
Metabolic diversity in Campylobacter jejuni enhances specific tissue colonization
Hofreuter, D., Novik, V., and J. E. Galán. 2008. Metabolic diversity in Campylobacter jejuni enhances specific tissue colonization. Cell Host & Microbe 4(5):425-33
Diversification of a Salmonella virulence effector protein function by ubiquitin-dependent differential localization
Patel, J. C., Hueffer, K., Lam, T. T. , J. E. Galán. 2009. Diversification of a Salmonella virulence effector protein function by ubiquitin-dependent differential localization. Cell 137(2):283-94.
A Sorting Platform Determines the Order of Protein Secretion in Bacterial Type III Systems
Lara-Tejero, M., J. Kato, S. Wagner, X. Liu, and J. E. Galán. 2011. A Sorting Platform Determines the Order of Protein Secretion in Bacterial Type III Systems. Science 331: 1188-1191.
A Rab32-depdent pathway controls Salmonella Typhi host restriction
Spano, S. and J. E. Galán. 2012. A Rab32-depdent pathway controls Salmonella Typhi host restriction. Science 338:960-963.
Conferring virulence: structure and function of the chimeric A2B5 typhoid toxin
Song, J., X. Gao, and J. E. Galán. 2013. Conferring virulence: structure and function of the chimeric A2B5 typhoid toxin. Nature 499, 350–354.
Full List of PubMed Publications
- Dietsche T, Tesfazgi Mebrhatu M, Brunner MJ, Abrusci P, Yan J, Franz-Wachtel M, Schärfe C, Zilkenat S, Grin I, Galán JE, Kohlbacher O, Lea S, Macek B, Marlovits TC, Robinson CV, Wagner S: Structural and Functional Characterization of the Bacterial Type III Secretion Export Apparatus. PLoS Pathog. 2016 Dec 15; 2016 Dec 15. PMID: 27977800
- Chang SJ, Song J, Galán JE: Receptor-Mediated Sorting of Typhoid Toxin during Its Export from Salmonella Typhi-Infected Cells. Cell Host Microbe. 2016 Nov 9. PMID: 27832592
- Galán JE: Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi. Proc Natl Acad Sci U S A. 2016 Jun 7; 2016 May 24. PMID: 27222578
- Zilkenat S, Franz-Wachtel M, Stierhof YD, Galán JE, Macek B, Wagner S: Determination of the Stoichiometry of the Complete Bacterial Type III Secretion Needle Complex Using a Combined Quantitative Proteomic Approach. Mol Cell Proteomics. 2016 May; 2016 Feb 21. PMID: 26900162
- Kamanova J, Sun H, Lara-Tejero M, Galán JE: The Salmonella Effector Protein SopA Modulates Innate Immune Responses by Targeting TRIM E3 Ligase Family Members. PLoS Pathog. 2016 Apr 8; 2016 Apr 8. PMID: 27058235
- Sun H, Kamanova J, Lara-Tejero M, Galán JE: A Family of Salmonella Type III Secretion Effector Proteins Selectively Targets the NF-κB Signaling Pathway to Preserve Host Homeostasis. PLoS Pathog. 2016 Mar 2; 2016 Mar 2. PMID: 26933955
- Song J, Wilhelm CL, Wangdi T, Maira-Litran T, Lee SJ, Raetz M, Sturge CR, Mirpuri J, Pei J, Grishin NV, McSorley SJ, Gewirtz AT, Bäumler AJ, Pier GB, Galán JE, Yarovinsky F: Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell. 2016 Feb 25. PMID: 26919416
- Tsou LK, Lara-Tejero M, RoseFigura J, Zhang ZJ, Wang YC, Yount JS, Lefebre M, Dossa PD, Kato J, Guan F, Lam W, Cheng YC, Galán JE, Hang HC: Antibacterial Flavonoids from Medicinal Plants Covalently Inactivate Type III Protein Secretion Substrates. J Am Chem Soc. 2016 Feb 24; 2016 Feb 16. PMID: 26847396
- Spanò S, Gao X, Hannemann S, Lara-Tejero M, Galán JE: A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP. Cell Host Microbe. 2016 Feb 10. PMID: 26867180
- Monjarás Feria JV, Lefebre MD, Stierhof YD, Galán JE, Wagner S: Role of autocleavage in the function of a type III secretion specificity switch protein in Salmonella enterica serovar Typhimurium. MBio. 2015 Oct 13; 2015 Oct 13. PMID: 26463164
- Kato J, Lefebre M, Galán JE: Structural Features Reminiscent of ATP-Driven Protein Translocases Are Essential for the Function of a Type III Secretion-Associated ATPase. J Bacteriol. 2015 Sep; 2015 Jul 13. PMID: 26170413
- Deng L, Song J, Gao X, Wang J, Yu H, Chen X, Varki N, Naito-Matsui Y, Galán JE, Varki A: Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi. Cell. 2014 Dec 4. PMID: 25480294
- Rathinavelan T, Lara-Tejero M, Lefebre M, Chatterjee S, McShan AC, Guo DC, Tang C, Galan JE, De Guzman RN: NMR model of PrgI-SipD interaction and its implications in the needle-tip assembly of the Salmonella type III secretion system. J Mol Biol. 2014 Aug 12; 2014 Jun 18. PMID: 24951833
- Gao B, Lara-Tejero M, Lefebre M, Goodman AL, Galán JE: Novel components of the flagellar system in epsilonproteobacteria. MBio. 2014 Jun 24; 2014 Jun 24. PMID: 24961693
- Kohler AC, Spanò S, Galán JE, Stebbins CE: Structural and enzymatic characterization of a host-specificity determinant from Salmonella. Acta Crystallogr D Biol Crystallogr. 2014 Feb; 2014 Jan 29. PMID: 24531472
- Lefebre MD, Galán JE: The inner rod protein controls substrate switching and needle length in a Salmonella type III secretion system. Proc Natl Acad Sci U S A. 2014 Jan 14; 2013 Dec 30. PMID: 24379359
- Galán JE, Lara-Tejero M, Marlovits TC, Wagner S: Bacterial type III secretion systems: specialized nanomachines for protein delivery into target cells. Annu Rev Microbiol. 2014; 2014 Jun 18. PMID: 25002086
- Spanò S, Galán JE: A novel anti-microbial function for a familiar Rab GTPase. Small GTPases. 2013 Oct-Dec; 2013 Dec 9. PMID: 24321888
- Song J, Gao X, Galán JE: Structure and function of the Salmonella Typhi chimaeric A(2)B(5) typhoid toxin. Nature. 2013 Jul 18; 2013 Jul 10. PMID: 23842500
- Hicks SW, Galán JE: Exploitation of eukaryotic subcellular targeting mechanisms by bacterial effectors. Nat Rev Microbiol. 2013 May. PMID: 23588250
- Chen X, Taylor DW, Fowler CC, Galan JE, Wang HW, Wolin SL: An RNA degradation machine sculpted by Ro autoantigen and noncoding RNA. Cell. 2013 Mar 28. PMID: 23540697
- Hodak H, Galán JE: A Salmonella Typhi homologue of bacteriophage muramidases controls typhoid toxin secretion. EMBO Rep. 2013 Jan; 2012 Nov 23. PMID: 23174673
- Carleton HA, Lara-Tejero M, Liu X, Galán JE: Engineering the type III secretion system in non-replicating bacterial minicells for antigen delivery. Nat Commun. 2013. PMID: 23481398
- Hannemann S, Gao B, Galán JE: Salmonella modulation of host cell gene expression promotes its intracellular growth. PLoS Pathog. 2013; 2013 Oct 3. PMID: 24098123
- Spanò S, Galán JE: A Rab32-dependent pathway contributes to Salmonella typhi host restriction. Science. 2012 Nov 16. PMID: 23162001
- Liu X, Gao B, Novik V, Galán JE: Quantitative Proteomics of Intracellular Campylobacter jejuni Reveals Metabolic Reprogramming. PLoS Pathog. 2012; 2012 Mar 8. PMID: 22412372
- Spanò S, Liu X, Galán JE: Proteolytic targeting of Rab29 by an effector protein distinguishes the intracellular compartments of human-adapted and broad-host Salmonella. Proc Natl Acad Sci U S A. 2011 Nov 8; 2011 Oct 31. PMID: 22042847
- Button JE, Galán JE: Regulation of chaperone/effector complex synthesis in a bacterial type III secretion system. Mol Microbiol. 2011 Sep; 2011 Aug 4. PMID: 21801239
- Mukherjee S, Liu X, Arasaki K, McDonough J, Galán JE, Roy CR: Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature. 2011 Aug 7; 2011 Aug 7. PMID: 21822290
- Hicks SW, Charron G, Hang HC, Galán JE: Subcellular targeting of Salmonella virulence proteins by host-mediated S-palmitoylation. Cell Host Microbe. 2011 Jul 21. PMID: 21767808
- Lara-Tejero M, Kato J, Wagner S, Liu X, Galán JE: A sorting platform determines the order of protein secretion in bacterial type III systems. Science. 2011 Mar 4; 2011 Feb 3. PMID: 21292939
- Song J, Willinger T, Rongvaux A, Eynon EE, Stevens S, Manz MG, Flavell RA, Galán JE: A mouse model for the human pathogen Salmonella typhi. Cell Host Microbe. 2010 Oct 21. PMID: 20951970
- Wagner S, Königsmaier L, Lara-Tejero M, Lefebre M, Marlovits TC, Galán JE: Organization and coordinated assembly of the type III secretion export apparatus. Proc Natl Acad Sci U S A. 2010 Oct 12; 2010 Sep 27. PMID: 20876096
- Novik V, Hofreuter D, Galán JE: Identification of Campylobacter jejuni genes involved in its interaction with epithelial cells. Infect Immun. 2010 Aug; 2010 Jun 1. PMID: 20515930
- Hicks SW, Galán JE: Hijacking the host ubiquitin pathway: structural strategies of bacterial E3 ubiquitin ligases. Curr Opin Microbiol. 2010 Feb; 2009 Dec 28. PMID: 20036613
- Novik V, Hofreuter D, Galán JE: Characterization of a Campylobacter jejuni VirK protein homolog as a novel virulence determinant. Infect Immun. 2009 Dec; 2009 Sep 21. PMID: 19797067
- Du F, Galán JE: Selective inhibition of type III secretion activated signaling by the Salmonella effector AvrA. PLoS Pathog. 2009 Sep; 2009 Sep 25. PMID: 19779561
- Bruno VM, Hannemann S, Lara-Tejero M, Flavell RA, Kleinstein SH, Galán JE: Salmonella Typhimurium type III secretion effectors stimulate innate immune responses in cultured epithelial cells. PLoS Pathog. 2009 Aug; 2009 Aug 7. PMID: 19662166
- Lara-Tejero M, Galán JE: Salmonella enterica serovar typhimurium pathogenicity island 1-encoded type III secretion system translocases mediate intimate attachment to nonphagocytic cells. Infect Immun. 2009 Jul; 2009 Apr 13. PMID: 19364837
- Galán JE: Common themes in the design and function of bacterial effectors. Cell Host Microbe. 2009 Jun 18. PMID: 19527884
- Patel JC, Hueffer K, Lam TT, Galán JE: Diversification of a Salmonella virulence protein function by ubiquitin-dependent differential localization. Cell. 2009 Apr 17. PMID: 19379694
- Hofreuter D, Novik V, Galán JE: Metabolic diversity in Campylobacter jejuni enhances specific tissue colonization. Cell Host Microbe. 2008 Nov 13. PMID: 18996343
- Spanò S, Galán JE: A novel pathway for exotoxin delivery by an intracellular pathogen. Curr Opin Microbiol. 2008 Feb; 2008 Feb 20. PMID: 18243772
- Spanò S, Ugalde JE, Galán JE: Delivery of a Salmonella Typhi exotoxin from a host intracellular compartment. Cell Host Microbe. 2008 Jan 17. PMID: 18191792
- Patel JC, Galán JE: Investigating the function of Rho family GTPases during Salmonella/host cell interactions. Methods Enzymol. 2008. PMID: 18374162
- Watson RO, Galán JE: Campylobacter jejuni survives within epithelial cells by avoiding delivery to lysosomes. PLoS Pathog. 2008 Jan. PMID: 18225954
- Galán JE: SnapShot: effector proteins of type III secretion systems. Cell. 2007 Jul 13. PMID: 17632065
- Haghjoo E, Galán JE: Identification of a transcriptional regulator that controls intracellular gene expression in Salmonella Typhi. Mol Microbiol. 2007 Jun. PMID: 17555437
- Watson RO, Novik V, Hofreuter D, Lara-Tejero M, Galán JE: A MyD88-deficient mouse model reveals a role for Nramp1 in Campylobacter jejuni infection. Infect Immun. 2007 Apr; 2006 Dec 28. PMID: 17194808
- Kamanaka M, Kim ST, Wan YY, Sutterwala FS, Lara-Tejero M, Galán JE, Harhaj E, Flavell RA: Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity. 2006 Dec; 2006 Nov 30. PMID: 17137799
- Galán JE, Wolf-Watz H: Protein delivery into eukaryotic cells by type III secretion machines. Nature. 2006 Nov 30. PMID: 17136086
- Patel JC, Galán JE: Differential activation and function of Rho GTPases during Salmonella-host cell interactions. J Cell Biol. 2006 Nov 6; 2006 Oct 30. PMID: 17074883
- Chen LM, Briones G, Donis RO, Galán JE: Optimization of the delivery of heterologous proteins by the Salmonella enterica serovar Typhimurium type III secretion system for vaccine development. Infect Immun. 2006 Oct. PMID: 16988261
- Hofreuter D, Tsai J, Watson RO, Novik V, Altman B, Benitez M, Clark C, Perbost C, Jarvie T, Du L, Galán JE: Unique features of a highly pathogenic Campylobacter jejuni strain. Infect Immun. 2006 Aug. PMID: 16861657
- Nishikawa H, Sato E, Briones G, Chen LM, Matsuo M, Nagata Y, Ritter G, Jäger E, Nomura H, Kondo S, Tawara I, Kato T, Shiku H, Old LJ, Galán JE, Gnjatic S: In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines. J Clin Invest. 2006 Jul; 2006 Jun 22. PMID: 16794737
- Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, Coyle AJ, Flavell RA, Galán JE: Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J Exp Med. 2006 Jun 12; 2006 May 22. PMID: 16717117
- Marlovits TC, Kubori T, Lara-Tejero M, Thomas D, Unger VM, Galán JE: Assembly of the inner rod determines needle length in the type III secretion injectisome. Nature. 2006 Jun 1. PMID: 16738660
- Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galán JE, Askenase PW, Flavell RA: Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity. 2006 Mar. PMID: 16546100
- Briones G, Hofreuter D, Galán JE: Cre reporter system to monitor the translocation of type III secreted proteins into host cells. Infect Immun. 2006 Feb. PMID: 16428755
- Patel JC, Rossanese OW, Galán JE: The functional interface between Salmonella and its host cell: opportunities for therapeutic intervention. Trends Pharmacol Sci. 2005 Nov; 2005 Sep 22. PMID: 16182381
- Akeda Y, Galán JE: Chaperone release and unfolding of substrates in type III secretion. Nature. 2005 Oct 6. PMID: 16208377
- Watson RO, Galán JE: Signal transduction in Campylobacter jejuni-induced cytokine production. Cell Microbiol. 2005 May. PMID: 15839895
- Galán JE: Bacterial toxins and the immune system: show me the in vivo targets. J Exp Med. 2005 Feb 7. PMID: 15699067
- Patel JC, Galán JE: Manipulation of the host actin cytoskeleton by Salmonella--all in the name of entry. Curr Opin Microbiol. 2005 Feb. PMID: 15694851
- Marlovits TC, Kubori T, Sukhan A, Thomas DR, Galán JE, Unger VM: Structural insights into the assembly of the type III secretion needle complex. Science. 2004 Nov 5. PMID: 15528446
- Hueffer K, Galán JE: Salmonella-induced macrophage death: multiple mechanisms, different outcomes. Cell Microbiol. 2004 Nov. PMID: 15469431
- Lara-Tejero M, Galán JE: A new twist in the hijacking of the actin-nucleating machinery. Mol Cell. 2004 Aug 27. PMID: 15327766
- Hernandez LD, Hueffer K, Wenk MR, Galán JE: Salmonella modulates vesicular traffic by altering phosphoinositide metabolism. Science. 2004 Jun 18. PMID: 15205533
- Akeda Y, Galán JE: Genetic analysis of the Salmonella enterica type III secretion-associated ATPase InvC defines discrete functional domains. J Bacteriol. 2004 Apr. PMID: 15060043
- Haghjoo E, Galán JE: Salmonella typhi encodes a functional cytolethal distending toxin that is delivered into host cells by a bacterial-internalization pathway. Proc Natl Acad Sci U S A. 2004 Mar 30. PMID: 15070766
- McKinney JS, Zhang H, Kubori T, Galán JE, Altman S: Disruption of type III secretion in Salmonella enterica serovar Typhimurium by external guide sequences. Nucleic Acids Res. 2004; 2004 Feb 3. PMID: 14762212
- Lee SH, Galán JE: Salmonella type III secretion-associated chaperones confer secretion-pathway specificity. Mol Microbiol. 2004 Jan. PMID: 14756788
- Hernandez LD, Pypaert M, Flavell RA, Galán JE: A Salmonella protein causes macrophage cell death by inducing autophagy. J Cell Biol. 2003 Dec 8. PMID: 14662750
- Lee SH, Galán JE: InvB is a type III secretion-associated chaperone for the Salmonella enterica effector protein SopE. J Bacteriol. 2003 Dec. PMID: 14645290
- Kubori T, Galán JE: Temporal regulation of salmonella virulence effector function by proteasome-dependent protein degradation. Cell. 2003 Oct 31. PMID: 14636560
- Sukhan A, Kubori T, Galán JE: Synthesis and localization of the Salmonella SPI-1 type III secretion needle complex proteins PrgI and PrgJ. J Bacteriol. 2003 Jun. PMID: 12754250
- Kubori T, Galán JE: Salmonella type III secretion-associated protein InvE controls translocation of effector proteins into host cells. J Bacteriol. 2002 Sep. PMID: 12169593
- Galán JE: The cell biology of microbial infections: coming of age. J Cell Biol. 2002 Aug 5; 2002 Aug 5. PMID: 12163462
- Kobayashi K, Hernandez LD, Galán JE, Janeway CA Jr, Medzhitov R, Flavell RA: IRAK-M is a negative regulator of Toll-like receptor signaling. Cell. 2002 Jul 26. PMID: 12150927
- Kobayashi K, Inohara N, Hernandez LD, Galán JE, Núñez G, Janeway CA, Medzhitov R, Flavell RA: RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature. 2002 Mar 14. PMID: 11894098
- Hughes EA, Galán JE: Immune response to Salmonella: location, location, location? Immunity. 2002 Mar. PMID: 11911817
- Lara-Tejero M, Galán JE: Cytolethal distending toxin: limited damage as a strategy to modulate cellular functions. Trends Microbiol. 2002 Mar. PMID: 11864825