The long-term objective is to determine how an enteropathogenic bacterium is able to enter and survive within animal cells. Enteropathogenic Yersinia are able to invade the epithelial cells of their hosts. This phenomenon will be investigated by studying how Yersinia pseudotuberculosis enters cultured cells and by investigating the consequences of invasion-defective mutations on pathogenesis in an animal model. The approach will be to analyze a genetic locus, called inv, that is encoded by this bacterium. To this end, the following goals will be pursued: 1) using a genetic analysis, it will be determined if invasion of cultured cells by Y. pseudotuberculosis requires the product of the inv locus; 2) the role that inv plays in the pathogenesis of disease will be analyzed using a mouse virulence assay; 3) all the products of this locus will be identified by performing DNA sequencing and by isolating nonsense mutations in the major gene product of this locus; 4) antibody will be raised to the major product of this locus, called p108, and this will be used to determine how this protein is localized in the bacterium; 5) the ligand encoded by Y. pseudotuberculosis that binds this bacterium to the animal cell will be identified by isolating mutations that eliminate this structure and by biochemically reconstituting the binding activity. Ingestion of bacteria by epithelial cells is the first step in the infection process of many enteropathogenic organisms. An understanding of how this occurs could allow the development of new chemotherapies that block this step in the infection process. In addition, identification of the components that allow a simple organism to enter an animal cell could result in new techniques to introduce therapeutic agents that would otherwise not be able to enter the host cell.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023538-02
Application #
3135792
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1986-06-01
Project End
1989-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Crimmins, Gregory T; Mohammadi, Sina; Green, Erin R et al. (2012) Identification of MrtAB, an ABC transporter specifically required for Yersinia pseudotuberculosis to colonize the mesenteric lymph nodes. PLoS Pathog 8:e1002828
Isberg, R R; Barnes, P (2001) Subversion of integrins by enteropathogenic Yersinia. J Cell Sci 114:21-28
Alrutz, M A; Srivastava, A; Wong, K W et al. (2001) Efficient uptake of Yersinia pseudotuberculosis via integrin receptors involves a Rac1-Arp 2/3 pathway that bypasses N-WASP function. Mol Microbiol 42:689-703
Isberg, R R; Hamburger, Z; Dersch, P (2000) Signaling and invasin-promoted uptake via integrin receptors. Microbes Infect 2:793-801
Krukonis, E S; Isberg, R R (2000) Integrin beta1-chain residues involved in substrate recognition and specificity of binding to invasin. Cell Microbiol 2:219-30
Dersch, P; Isberg, R R (2000) An immunoglobulin superfamily-like domain unique to the Yersinia pseudotuberculosis invasin protein is required for stimulation of bacterial uptake via integrin receptors. Infect Immun 68:2930-8
Dersch, P; Isberg, R R (1999) A region of the Yersinia pseudotuberculosis invasin protein enhances integrin-mediated uptake into mammalian cells and promotes self-association. EMBO J 18:1199-213
Alrutz, M A; Isberg, R R (1998) Involvement of focal adhesion kinase in invasin-mediated uptake. Proc Natl Acad Sci U S A 95:13658-63
Krukonis, E S; Dersch, P; Eble, J A et al. (1998) Differential effects of integrin alpha chain mutations on invasin and natural ligand interaction. J Biol Chem 273:31837-43
Krukonis, E S; Isberg, R R (1998) SWIM analysis allows rapid identification of residues involved in invasin-mediated bacterial uptake. Gene 211:109-16

Showing the most recent 10 out of 33 publications