Salmonella enter intestinal epithelial cells during infection of their hosts. Interestingly, bacterial invasion into host cells is not an enduring feature of Salmonella pathogenesis. The ability of Salmonella to enter non phagocytic cells appears to change in vivo. The objective of this application is to investigate the molecular mechanisms which control S. typhimurium invasiveness. These studies will lead to a better understanding of how Salmonella decide to infect non-phagocytic host cells during infection. The main goal of this project is to investigate the role of HilA in the regulation of Salmonella invasion genes and pathogenesis. HilA is a transcriptional activator that regulates the expression of many, if not all, invasion genes in S. typhimurium. Many environmental and regulatory factors control the expression of hilA and, thus, indirectly control the expression of invasion genes. The complex regulation of hilA and invasion genes appears to be an important mechanism to limit bacterial invasiveness during infection. The hilA promoter and the transcriptional regulators that directly control the hilA promoter will be characterized to understand how environmental conditions regulate hilA expression. Invasion gene promoters and the HilA protein will be examined to discern how HilA coordinately activates invasion genes. Post-translational modulation of HilA activity may provide an additional level of regulation. Studies are proposed to determine whether and how the activity of HilA might be modulated. The importance of hilA and invasion gene regulation for pathogenesis will be tested by analysis of bacterial gene expression and invasiveness during infection. Salmonella infection remains a national and worldwide health problem. Ultimately, chemotherapies might be designed to inhibit the expression of invasion genes and prevent this early step in Salmonella infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033444-06
Application #
2886804
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1994-05-01
Project End
2002-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Schechter, Lisa M; Jain, Sumita; Akbar, Samina et al. (2003) The small nucleoid-binding proteins H-NS, HU, and Fis affect hilA expression in Salmonella enterica serovar Typhimurium. Infect Immun 71:5432-5
Rodriguez, Christine R; Schechter, Lisa M; Lee, Catherine A (2002) Detection and characterization of the S. typhimurium HilA protein. BMC Microbiol 2:31
Lostroh, C P; Lee, C A (2001) The Salmonella pathogenicity island-1 type III secretion system. Microbes Infect 3:1281-91
Lostroh, C P; Lee, C A (2001) The HilA box and sequences outside it determine the magnitude of HilA-dependent activation of P(prgH) from Salmonella pathogenicity island 1. J Bacteriol 183:4876-85
Lucas, R L; Lee, C A (2001) Roles of hilC and hilD in regulation of hilA expression in Salmonella enterica serovar Typhimurium. J Bacteriol 183:2733-45
Lucas, R L; Lee, C A (2000) Unravelling the mysteries of virulence gene regulation in Salmonella typhimurium. Mol Microbiol 36:1024-33
Lostroh, C P; Bajaj, V; Lee, C A (2000) The cis requirements for transcriptional activation by HilA, a virulence determinant encoded on SPI-1. Mol Microbiol 37:300-15
Murray, R A; Lee, C A (2000) Invasion genes are not required for Salmonella enterica serovar typhimurium to breach the intestinal epithelium: evidence that salmonella pathogenicity island 1 has alternative functions during infection. Infect Immun 68:5050-5
Schechter, L M; Damrauer, S M; Lee, C A (1999) Two AraC/XylS family members can independently counteract the effect of repressing sequences upstream of the hilA promoter. Mol Microbiol 32:629-42
Lee, C A (1997) Type III secretion systems: machines to deliver bacterial proteins into eukaryotic cells? Trends Microbiol 5:148-56

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