Listeria monocytogenes (L. m.) causes serious invasive diseases in humans and animals, with a human case mortality rate of approximately 20%. One goal of the US Dept. of Health and Human Services Healthy People 2010 Initiative is to reduce human listeriosis cases by 50%. The long-term objective of our research program is to contribute to that end through identification of factors that influence L. m. pathogenesis, which ultimately will enable development of novel and effective intervention strategies for preventing listerial infections. The work proposed in this application is designed to test the specific hypotheses that (i) the sigma/B general stress response system in gram-positive bacterial pathogens (and specifically in L. monocytogenes) provides a key transcriptional regulatory mechanism that facilitates environmental survival and virulence through induction of stress response genes; and that (ii) bacterial stress response systems contribute to pathogenesis by responding to specific environments, including those encountered in the host, through initiation of stress response and virulence gene expression (e.g., prfA).
The specific aims of these studies are to: (1) Define the L. m. sigmaB regulon through proteomic and genetic approaches. (2) Determine sigmaB regulon expression patterns under environmental stress conditions, sigma/B -dependent gene expression patterns will be evaluated using microarrays and reporter (-3) Measure sigmaB-dependent gene expression during host cell infection. Reporter fusions to selected sigmaB-dependent genes (e.g., prfA) in wildtype L. m. and selected null mutant strains (e.g., AsigB) will be used to identify gene expression patterns during cellular infection in tissue culture models. (4) Characterize deltasigmaB mutant virulence in tissue culture and animal models. At the conclusion of these studies, we will have developed an understanding of the contribution of cyB and the sigmaB-dependent stress response system to L. monocytogenes environmental survival and infection. More broadly, L. monocytogenes will serve as a model system for examining the role of alternative sigma factor-directed general stress response systems in survival and pathogenesis of gram-positive food-borne pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052151-04
Application #
7005379
Study Section
Special Emphasis Panel (ZRG1-BM-1 (05))
Program Officer
Mills, Melody
Project Start
2003-08-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2006
Total Cost
$282,550
Indirect Cost
Name
Cornell University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Liu, Yichang; Orsi, Renato H; Boor, Kathryn J et al. (2017) Home Alone: Elimination of All but One Alternative Sigma Factor in Listeria monocytogenes Allows Prediction of New Roles for ?B. Front Microbiol 8:1910
Guldimann, Claudia; Boor, Kathryn J; Wiedmann, Martin et al. (2016) Resilience in the Face of Uncertainty: Sigma Factor B Fine-Tunes Gene Expression To Support Homeostasis in Gram-Positive Bacteria. Appl Environ Microbiol 82:4456-4469
Liu, Yichang; Orsi, Renato Hohl; Boor, Kathryn Jean et al. (2016) An advanced bioinformatics approach for analyzing RNA-seq data reveals sigma H-dependent regulation of competence genes in Listeria monocytogenes. BMC Genomics 17:115
Orsi, Renato H; Bergholz, Teresa M; Wiedmann, Martin et al. (2015) The Listeria monocytogenes strain 10403S BioCyc database. Database (Oxford) 2015:
Bergholz, Teresa M; Moreno Switt, Andrea I; Wiedmann, Martin (2014) Omics approaches in food safety: fulfilling the promise? Trends Microbiol 22:275-81
Oliver, H F; Orsi, R H; Wiedmann, M et al. (2013) ?(B) plays a limited role in the ability of Listeria monocytogenes strain F2365 to survive oxidative and acid stress and in its virulence characteristics. J Food Prot 76:2079-86
Mujahid, Sana; Orsi, Renato H; Boor, Kathryn J et al. (2013) Protein level identification of the Listeria monocytogenes sigma H, sigma L, and sigma C regulons. BMC Microbiol 13:156
Mujahid, S; Orsi, R H; Vangay, P et al. (2013) Refinement of the Listeria monocytogenes ?B regulon through quantitative proteomic analysis. Microbiology 159:1109-19
Ringus, Daina L; Gaballa, Ahmed; Helmann, John D et al. (2013) Fluoro-phenyl-styrene-sulfonamide, a novel inhibitor of ýýB activity, prevents the activation of ýýB by environmental and energy stresses in Bacillus subtilis. J Bacteriol 195:2509-17
Mujahid, Sana; Bergholz, Teresa M; Oliver, Haley F et al. (2012) Exploration of the role of the non-coding RNA SbrE in L. monocytogenes stress response. Int J Mol Sci 14:378-93

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