The principal features of Shigella pathogenicity are its ability to invade epithelial cells and multiply within the cells. Expression of Shigella virulence is temperature regulated, the organism being invasive when grown at 37 degrees Celsius but phenotypically avirulent (non-invasive) when grown at 30 degrees Celsius. The proposed project will examine the mechanism by which Shigella regulates expression of its virulence (vir) genes in response to growth temperature. These experiments are designed to: 1) isolate lactose (lac) operon fusions to a variety of temperature regulated vir genes in Shigella flexneri; 2) isolate mutations affecting the temperature regulation of these vir genes; and, 3) elucidate the mechanism of action of the regulatory gene products. The hypothesis that Shigella vir genes constitute a regulon which is globally controlled by a regulatory mechanism responding to temperature changes will be tested. Methodology will include: generating vir::lac operon fusions by use of a lambda placMu vector; cloning of mutant and wild type regulatory genes; cloning of vir::lac fusions to isolate operator-promoter regions; and, biochemical and molecular analysis of regulatory gene products. Results of these studies will improve our understanding of the pathogenicity of Shigella and its regulation. The vir::lac fusions will also contribute to our long term objectives by serving as markers for cloning native vir genes with the goal of identifying gene products which can be tested as antigens in an anti-Shigella vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024656-02
Application #
3137799
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1988-12-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817
Fogolari, Marta; Mavian, Carla; Angeletti, Silvia et al. (2018) Distribution and characterization of Shiga toxin converting temperate phages carried by Shigella flexneri in Hispaniola. Infect Genet Evol 65:321-328
Lampel, Keith A; Formal, Samuel B; Maurelli, Anthony T (2018) A Brief History of Shigella. EcoSal Plus 8:
Bliven, Kimberly A; Maurelli, Anthony T (2016) Evolution of Bacterial Pathogens Within the Human Host. Microbiol Spectr 4:
Gray, M D; Lacher, D W; Leonard, S R et al. (2015) Prevalence of Shiga toxin-producing Shigella species isolated from French travellers returning from the Caribbean: an emerging pathogen with international implications. Clin Microbiol Infect 21:765.e9-765.e14
Gray, Miranda D; Lampel, Keith A; Strockbine, Nancy A et al. (2014) Clinical isolates of Shiga toxin 1a-producing Shigella flexneri with an epidemiological link to recent travel to HispaƱiola. Emerg Infect Dis 20:1669-77
Emanuele, Anthony A; Adams, Nancy E; Chen, Yi-Chen et al. (2014) Potential novel antibiotics from HTS targeting the virulence-regulating transcription factor, VirF, from Shigella flexneri. J Antibiot (Tokyo) 67:379-86
Bliven, Kimberly A; Maurelli, Anthony T (2012) Antivirulence genes: insights into pathogen evolution through gene loss. Infect Immun 80:4061-70
Faherty, Christina S; Merrell, D Scott; Semino-Mora, Cristina et al. (2010) Microarray analysis of Shigella flexneri-infected epithelial cells identifies host factors important for apoptosis inhibition. BMC Genomics 11:272
Zurawski, Daniel V; Mumy, Karen L; Faherty, Christina S et al. (2009) Shigella flexneri type III secretion system effectors OspB and OspF target the nucleus to downregulate the host inflammatory response via interactions with retinoblastoma protein. Mol Microbiol 71:350-68
Faherty, Christina S; Maurelli, Anthony T (2009) Spa15 of Shigella flexneri is secreted through the type III secretion system and prevents staurosporine-induced apoptosis. Infect Immun 77:5281-90

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