EXCEED THE SPACE PROVIDED. Staphylococcus aureus is a major human pathogen, which can cause serious infections. The organism has become increasingly problematic recently due to emerging multiple-drug resistance strains that are unresponsive to antibiotic treatment. New methods of treatment are therefore urgently needed. Almost all strains of S. aureus produce capsular polysaccharide, which have been classified into 11 setotypes. Type 5 and 8 capsules, which are structurally and genetically similar, are predominant capsules and thus have been used as targets for vaccine development. Recent studies, including our own, have shown that these capsules act as antiphagocytic virulence factors and thereby play an important role in staphylococcal pathogenesis. The produciton of these capsules are influenced by environmental stimuli, however, very little is known about their regulation at the molecular level. Recently, we have characterized the promoter region controlling the expression type 8 capsule genes and have shown that type 5 and 8 capsules are regulated by several known regulators. We have also genetically identified several putative regulatory genes. These results therefore suggest that type 5 and 8 capsules are regulated by a complex regulatory network. In this proposal, we will focus on the regulatory aspect of capsule expression. We propose to accomplish three specific aims: (i) to characterize the regulatory genes involved in the control of capsule production by molecular approaches; (ii) to study the interactions between regulators by genetic and biochemical analyses of mutants deficient in regulatory genes to elucidate regulatory networking; (iii) to investigate the regulation of capsules by environmental stimuli by focusing on carbon dioxide effect both in vitro and in vivo. The successful completion of the studies outlined in this application will undoubtedly unveil the regulatory mechanism controlling the expression of these important virulence factors, which will provide a firm basis for developing new methods of treating staphylocuccal infections. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037027-12
Application #
6824905
Study Section
Special Emphasis Panel (ZRG1-BM-1 (03))
Program Officer
Peters, Kent
Project Start
1994-12-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
12
Fiscal Year
2005
Total Cost
$248,500
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Gupta, Ravi Kr; Luong, Thanh T; Lee, Chia Y (2015) RNAIII of the Staphylococcus aureus agr system activates global regulator MgrA by stabilizing mRNA. Proc Natl Acad Sci U S A 112:14036-41
Medema, Marnix H; Kottmann, Renzo; Yilmaz, Pelin et al. (2015) Minimum Information about a Biosynthetic Gene cluster. Nat Chem Biol 11:625-31
Atwood, Danielle N; Loughran, Allister J; Courtney, Ashleah P et al. (2015) Comparative impact of diverse regulatory loci on Staphylococcus aureus biofilm formation. Microbiologyopen 4:436-51
Beenken, Karen E; Mrak, Lara N; Zielinska, Agnieszka K et al. (2014) Impact of the functional status of saeRS on in vivo phenotypes of Staphylococcus aureus?sarA mutants. Mol Microbiol 92:1299-312
Prax, Marcel; Lee, Chia Y; Bertram, Ralph (2013) An update on the molecular genetics toolbox for staphylococci. Microbiology 159:421-35
Gupta, Ravi Kr; Alba, Jimena; Xiong, Yan Q et al. (2013) MgrA activates expression of capsule genes, but not the ?-toxin gene in experimental Staphylococcus aureus endocarditis. J Infect Dis 208:1841-8
Graham, Justin W; Lei, Mei G; Lee, Chia Y (2013) Trapping and identification of cellular substrates of the Staphylococcus aureus ClpC chaperone. J Bacteriol 195:4506-16
Lei, Mei G; Cue, David; Alba, Jimena et al. (2012) A single copy integration vector that integrates at an engineered site on the Staphylococcus aureus chromosome. BMC Res Notes 5:5
Cue, David; Lei, Mei G; Lee, Chia Y (2012) Genetic regulation of the intercellular adhesion locus in staphylococci. Front Cell Infect Microbiol 2:38
Zielinska, Agnieszka K; Beenken, Karen E; Joo, Hwang-Soo et al. (2011) Defining the strain-dependent impact of the Staphylococcal accessory regulator (sarA) on the alpha-toxin phenotype of Staphylococcus aureus. J Bacteriol 193:2948-58

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