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Michelle Dziejman

TitleAssociate Professor
InstitutionSchool of Medicine and Dentistry
DepartmentMicrobiology and Immunology
AddressUniversity of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 672
Rochester NY 14642
 
 Awards And Honors
      NIH NRSA
 
 Overview
Research Focus
Type Three Secretion System mediated pathogenesis of V. cholerae
Research Overview
Vibrio cholerae is a diverse species found in aquatic environments worldwide, and it is the causative agent of the severe diarrheal disease known as cholera. Epidemic disease in Asia and South America is currently caused only by strains of the O1 or O139 serogroup of V. cholerae. However, a significant amount of world wide, sporadic disease is caused by strains of other serogroups, collectively called non-O1/non-O139 strains. Ribotyping and comparative genomic analyses have shown that these strains are very diverse both phylogenetically and in their genetic content compared to strains of the O1 and O139 serogroups. Unlike epidemic strains, the majority of non-O1/non-O139 strains do not carry the well characterized virulence factors for colonization (toxin co-regulated pilus, TCP) and cholera toxin (CT) production. It is presumed that pathogenic non-O1/non-O139 isolates have acquired novel virulence factors that confer the ability to colonize and cause disease in a TCP/CT independent manner. However, these strains remain largely uncharacterized.
AM-19226 is a clinically isolated, O39 serogroup strain of V. cholerae that does not carry the genes encoding TCP or CT. However, whole genome sequencing of AM-19226 has identified open reading frames (ORFs) having significant similarity to genes encoding the structural components of a Type Three Secretion System (T3SS). These ORFs, named vcs, lie within a ~60kb pathogenicity island that has been found in other non-O1/non-O139 strains. A wide variety of gram-negative, pathogenic bacteria use TTSSs as a conserved mechanism to translocate multiple virulence factors, referred to as T3SS effector proteins, directly into the cytosol of eukaryotic cells. We therefore postulate that the vcs genes represent a previously unidentified mechanism for host cell interaction acquired by V. cholerae. Also within this island are two open reading frames predicted to encode proteins having sequence similarity to ToxR, an important player in the network of regulatory proteins that govern the expression of virulence factors in epidemic O1 and O139 serogroup strains. Although the amino acid sequences of proteins encoding the structural components are highly conserved among T3SSs of different organisms, the sequences of effector proteins typically share limited or no homology. Effector proteins are therefore often unique to a specific T3SS, and their interactions with eukaryotic host cell proteins serve to elicit distinct phenotypes beneficial for the particular bacterial pathogen.
In order to understanding the scope of molecular mechanisms responsible for TTSS mediated disease, we are working to:

1. understand the role of the ToxR paralogs and ToxR itself in T3SS related gene expression.
2. identify in vitro conditions that promote expression of the T3SS genes.
3. identify effector proteins that are required during infection to provide functions critical for colonization and disease.

To accomplish these goals we use several experimental approaches, including genetic and molecular techniques complimented by in vitro mammalian cell culture model systems. In addition, we collaborate with Dr. J. Scott Butler (also in the Dept. of Microbiology & Immunology) in using S. cerevisiae as a model system for the identification of effector proteins and the analyses of their molecular interactions with components of the eukaryotic host machinery.

 
 Selected Publications
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  1. Chaand M, Dziejman M. Vibrio cholerae VttRA and VttRB Regulatory Influences Extend beyond the Type 3 Secretion System Genomic Island. J Bacteriol. 2013 May; 195(10):2424-36.
    View in: PubMed
  2. Miller KA, Hamilton E, Dziejman M. The Vibrio cholerae trh Gene Is Coordinately Regulated In Vitro with Type III Secretion System Genes by VttRA/VttRB but Does Not Contribute to Caco2-BBE Cell Cytotoxicity. Infect Immun. 2012 Dec; 80(12):4444-55.
    View in: PubMed
  3. Valentino MD, Abdul-Alim CS, Maben ZJ, Skrombolas D, Hensley LL, Kawula TH, Dziejman M, Lord EM, Frelinger JA, Frelinger JG. A broadly applicable approach to T cell epitope identification: application to improving tumor associated epitopes and identifying epitopes in complex pathogens. J Immunol Methods. 2011 Oct 28; 373(1-2):111-26.
    View in: PubMed
  4. Alam A, Miller KA, Chaand M, Butler JS, Dziejman M. Identification of Vibrio cholerae type III secretion system effector proteins. Infect Immun. 2011 Apr; 79(4):1728-40.
    View in: PubMed
  5. Alam A, Tam V, Hamilton E, Dziejman M. vttRA and vttRB Encode ToxR family proteins that mediate bile-induced expression of type three secretion system genes in a non-O1/non-O139 Vibrio cholerae strain. Infect Immun. 2010 Jun; 78(6):2554-70.
    View in: PubMed
  6. Tam VC, Serruto D, Dziejman M, Brieher W, Mekalanos JJ. A type III secretion system in Vibrio cholerae translocates a formin/spire hybrid-like actin nucleator to promote intestinal colonization. Cell Host Microbe. 2007 Apr 19; 1(2):95-107.
    View in: PubMed
  7. Faruque SM, Tam VC, Chowdhury N, Diraphat P, Dziejman M, Heidelberg JF, Clemens JD, Mekalanos JJ, Nair GB. Genomic analysis of the Mozambique strain of Vibrio cholerae O1 reveals the origin of El Tor strains carrying classical CTX prophage. Proc Natl Acad Sci U S A. 2007 Mar 20; 104(12):5151-6.
    View in: PubMed
  8. Larocque RC, Harris JB, Dziejman M, Li X, Khan AI, Faruque AS, Faruque SM, Nair GB, Ryan ET, Qadri F, Mekalanos JJ, Calderwood SB. Transcriptional profiling of Vibrio cholerae recovered directly from patient specimens during early and late stages of human infection. Infect Immun. 2005 Aug; 73(8):4488-93.
    View in: PubMed
  9. Dziejman M, Serruto D, Tam VC, Sturtevant D, Diraphat P, Faruque SM, Rahman MH, Heidelberg JF, Decker J, Li L, Montgomery KT, Grills G, Kucherlapati R, Mekalanos JJ. Genomic characterization of non-O1, non-O139 Vibrio cholerae reveals genes for a type III secretion system. Proc Natl Acad Sci U S A. 2005 Mar 1; 102(9):3465-70.
    View in: PubMed
  10. Faruque SM, Chowdhury N, Kamruzzaman M, Dziejman M, Rahman MH, Sack DA, Nair GB, Mekalanos JJ. Genetic diversity and virulence potential of environmental Vibrio cholerae population in a cholera-endemic area. Proc Natl Acad Sci U S A. 2004 Feb 17; 101(7):2123-8.
    View in: PubMed
  11. Bina J, Zhu J, Dziejman M, Faruque S, Calderwood S, Mekalanos J. ToxR regulon of Vibrio cholerae and its expression in vibrios shed by cholera patients. Proc Natl Acad Sci U S A. 2003 Mar 4; 100(5):2801-6.
    View in: PubMed
  12. Xu Q, Dziejman M, Mekalanos JJ. Determination of the transcriptome of Vibrio cholerae during intraintestinal growth and midexponential phase in vitro. Proc Natl Acad Sci U S A. 2003 Feb 4; 100(3):1286-91.
    View in: PubMed
  13. Dufour JH, Dziejman M, Liu MT, Leung JH, Lane TE, Luster AD. IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J Immunol. 2002 Apr 1; 168(7):3195-204.
    View in: PubMed
  14. Zhu J, Miller MB, Vance RE, Dziejman M, Bassler BL, Mekalanos JJ. Quorum-sensing regulators control virulence gene expression in Vibrio cholerae. Proc Natl Acad Sci U S A. 2002 Mar 5; 99(5):3129-34.
    View in: PubMed
  15. Dziejman M, Balon E, Boyd D, Fraser CM, Heidelberg JF, Mekalanos JJ. Comparative genomic analysis of Vibrio cholerae: genes that correlate with cholera endemic and pandemic disease. Proc Natl Acad Sci U S A. 2002 Feb 5; 99(3):1556-61.
    View in: PubMed
  16. Yang OO, Swanberg SL, Lu Z, Dziejman M, McCoy J, Luster AD, Walker BD, Herrmann SH. Enhanced inhibition of human immunodeficiency virus type 1 by Met-stromal-derived factor 1beta correlates with down-modulation of CXCR4. J Virol. 1999 Jun; 73(6):4582-9.
    View in: PubMed
  17. Sauty A, Dziejman M, Taha RA, Iarossi AS, Neote K, Garcia-Zepeda EA, Hamid Q, Luster AD. The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells. J Immunol. 1999 Mar 15; 162(6):3549-58.
    View in: PubMed
  18. Dziejman M, Kolmar H, Fritz HJ, Mekalanos JJ. ToxR co-operative interactions are not modulated by environmental conditions or periplasmic domain conformation. Mol Microbiol. 1999 Jan; 31(1):305-17.
    View in: PubMed
  19. Agostini C, Cassatella M, Zambello R, Trentin L, Gasperini S, Perin A, Piazza F, Siviero M, Facco M, Dziejman M, Chilosi M, Qin S, Luster AD, Semenzato G. Involvement of the IP-10 chemokine in sarcoid granulomatous reactions. J Immunol. 1998 Dec 1; 161(11):6413-20.
    View in: PubMed
  20. Dziejman M, Mekalanos JJ. Analysis of membrane protein interaction: ToxR can dimerize the amino terminus of phage lambda repressor. Mol Microbiol. 1994 Aug; 13(3):485-94.
    View in: PubMed
  21. Mirels L, Kopec L, Yagil C, Dickinson DP, Dziejman M, Tabak LA. Expression of glutamine/glutamic acid-rich proteins in rat submandibular glands. Arch Oral Biol. 1990; 35(1):1-5.
    View in: PubMed

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