Research Interests | CV | Publications

Research Interests

Our laboratory is interested in the molecular mechanisms used by Salmonella typhimurium to modulate expression of its genes in response to environmental stimuli (such as those experienced during infection) and to enter and survive within cells of animal hosts. An understanding of these processes may lead to novel therapeutic, prevention and diagnostic strategies. Our laboratory uses a combination of molecular, genetic, biochemical and cell biological approaches to investigate four aspects of the facultative intracellular pathogen S. typhimurium: (1) Signal transduction and transcriptional regulation of virulence genes. (2) Invasion of and survival within host cells. (3) Mechanisms of resistance to antimicrobial peptides. (4) Evolutionry origins of Salmonella virulencer.

We have discovered the first and only signal transduction cascade that responds to extracellular magnesium. Changes in the levels of extracellular cations detected by the sensor protein PhoQ are transmitted to the transcription factor factor PhoP so it can modulate expression of a variety of virulence genes, allowing Salmonella to mount an adaptive response. The PhoP/PhoQ system also interacts with the PmrA/PmrB two-component system, which governs modifications in the LPS that mediate resistance to the antibiotic polymyxin B. We are interested in (a) identifying PhoP-regulated loci, (b) characterizing the divalent cation binding sites in the sensor protein PhoQ, (c) understanding the mechanism of signal transduction by which binding of magnesium to the sensing domain of PhoQ changes the enzymatic activity of its enzymatic domain on the other side of the membrane, and (d) investigating the regulatory interactions between the PhoP/PhoQ and PmrA/PmrB systems.

We are also interested in the molecular determinants that allow Salmonella to survive within host phagocytic cells. We are investigating (a) a novel transcriptional regulator and secretion apparatus that are essential for macrophage survival, and (b) the mechanisms used by Salmonella to resist killing by microbicidal peptides produced in several host tissues. Finally, to understand the ability of Salmonella to survive within unique environments, we are analyzing the structure, function and evolutionary origin of genes that are specific to Salmonella. This work has led to the discovery of several pathogenicity islands, chromosomal DNA segments that harbor clusters of virulencegenes not found in related, non-pathogenicspecies.

CV

Publications

1. Shin D, Lee EJ, Huang H, Groisman EA. Related Articles, Links
   A positive feedback loop promotes transcription surge that jump-starts Salmonella virulence circuit.
   Science. 2006 Dec 8;314(5805):1607-9.
2. Tu X, Latifi T, Bougdour A, Gottesman S, Groisman EA. Related Articles, Links
   The PhoP/PhoQ two-component system stabilizes the alternative sigma factor RpoS in Salmonella enterica.
   Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13503-8. Epub 2006 Aug 28.
3. Groisman EA, Mouslim C. Related Articles, Links
   Sensing by bacterial regulatory systems in host and non-host environments.
   Nat Rev Microbiol. 2006 Sep;4(9):705-9. Epub 2006 Aug 7.
4. Nishino K, Hsu FF, Turk J, Cromie MJ, Wosten MM, Groisman EA. Related Articles, Links
   Identification of the lipopolysaccharide modifications controlled by the Salmonella PmrA/PmrB system mediating resistance to Fe(III) and Al(III).
   Mol Microbiol. 2006 Aug;61(3):645-54. Epub 2006 Jun 27.
5. Cromie MJ, Shi Y, Latifi T, Groisman EA. Related Articles, Links
   An RNA sensor for intracellular Mg(2+).
   Cell. 2006 Apr 7;125(1):71-84.
6. Delgado MA, Mouslim C, Groisman EA. Related Articles, Links
   The PmrA/PmrB and RcsC/YojN/RcsB systems control expression of the Salmonella O-antigen chain length determinant.
   Mol Microbiol. 2006 Apr;60(1):39-50.
7. Nishino K, Latifi T, Groisman EA. Related Articles, Links
   Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium.
   Mol Microbiol. 2006 Jan;59(1):126-41.
8. Zwir I, Huang H, Groisman EA. Related Articles, Links
   Analysis of differentially-regulated genes within a regulatory network by GPS genome navigation.
   Bioinformatics. 2005 Nov 15;21(22):4073-83. Epub 2005 Sep 13.
9. Bijlsma JJ, Groisman EA. Related Articles, Links
   The PhoP/PhoQ system controls the intramacrophage type three secretion system of Salmonella enterica.
   Mol Microbiol. 2005 Jul;57(1):85-96.
10. Hsu FF, Turk J, Rhoades ER, Russell DG, Shi Y, Groisman EA. Related Articles, Links
    Structural characterization of cardiolipin by tandem quadrupole and multiple-stage quadrupole ion-trap mass spectrometry with electrospray ionization.
    J Am Soc Mass Spectrom. 2005 Apr;16(4):491-504.
11. Groisman EA, Casadesus J. Related Articles, Links
    The origin and evolution of human pathogens.
    Mol Microbiol. 2005 Apr;56(1):1-7. Review.
12. Winfield MD, Latifi T, Groisman EA. Related Articles, Links
    Transcriptional regulation of the 4-amino-4-deoxy-L-arabinose biosynthetic genes in Yersinia pestis.
    J Biol Chem. 2005 Apr 15;280(15):14765-72. Epub 2005 Feb 14.
13. Zwir I, Shin D, Kato A, Nishino K, Latifi T, Solomon F, Hare JM, Huang H, Groisman EA. Related Articles, Links
    Dissecting the PhoP regulatory network of Escherichia coli and Salmonella enterica.
    Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2862-7. Epub 2005 Feb 9.
14. Winfield MD, Groisman EA. Related Articles, Links
    Phenotypic differences between Salmonella and Escherichia coli resulting from the disparate regulation of homologous genes.
    Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17162-7. Epub 2004 Nov 29.
15. Shin D, Groisman EA. Related Articles, Links
    Signal-dependent binding of the response regulators PhoP and PmrA to their target promoters in vivo.
    J Biol Chem. 2005 Feb 11;280(6):4089-94. Epub 2004 Nov 29.
16. Mouslim C, Delgado M, Groisman EA. Related Articles, Links
    Activation of the RcsC/YojN/RcsB phosphorelay system attenuates Salmonella virulence.
    Mol Microbiol. 2004 Oct;54(2):386-95.
17. Kato A, Groisman EA. Related Articles, Links
    Connecting two-component regulatory systems by a protein that protects a response regulator from dephosphorylation by its cognate sensor.
    Genes Dev. 2004 Sep 15;18(18):2302-13.
18. Shi Y, Cromie MJ, Hsu FF, Turk J, Groisman EA. Related Articles, Links
    PhoP-regulated Salmonella resistance to the antimicrobial peptides magainin 2 and polymyxin B.
    Mol Microbiol. 2004 Jul;53(1):229-41.
19. Shi Y, Latifi T, Cromie MJ, Groisman EA. Related Articles, Links
    Transcriptional control of the antimicrobial peptide resistance ugtL gene by the Salmonella PhoP and SlyA regulatory proteins.
    J Biol Chem. 2004 Sep 10;279(37):38618-25. Epub 2004 Jun 18.
20. Lee H, Hsu FF, Turk J, Groisman EA. Related Articles, Links
    The PmrA-regulated pmrC gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica.
    J Bacteriol. 2004 Jul;186(13):4124-33.