The group A streptococcus (Streptococcus pyogenes, GAS) is a bacterial pathogen of significant medical importance that has evolved specific mechanisms to express an appropriate set of virulence attributes upon encountering a particular host tissue. Mga is a DNA-binding protein of GAS that regulates the transcription of several key virulence genes encoding products essential for colonization and immune evasion of GAS in the host in response to the growth phase and other environmental conditions. Furthermore, orthologues of Mga involved in virulence gene regulation are being found in many other pathogenic streptococci. Thus, Mga provides an excellent system to study global regulatory networks involved in GAS pathogenesis as well as a paradigm for a new family of virulence regulators in Gram-positive pathogens. The overall objectives of this renewal application are (a) to continue a structure/function analysis of Mga and its promoter to better understand the mechanisms by which this key GAS virulence regulator contributes to streptococcal disease, and (b) improve our general understanding of global regulatory pathways that interact to broadly control virulence in these and other important pathogens.
The specific aims of this project are (1) To characterize the predicted functional domains within Mga for their role in signal transduction and Mga-dependent transcriptional regulation (2) To examine the mechanisms of Mga-dependent auto-activation and Mga- independent regulation at the mga promoter (Pmga) (3) To establish the role for AmrA and potentially other upstream factors in the growth phase control of mga and the Mga regulon and (4) To investigate how growth phase regulation of the Mga regulon contributes to virulence during GAS infection in mice. A thorough understanding of Mga and its regulation described here will contribute valuable new insights into global virulence regulation not only in GAS, but in other Gram-positive pathogens as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047928-10
Application #
7739504
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
GU, Xin-Xing
Project Start
2000-07-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
10
Fiscal Year
2010
Total Cost
$280,078
Indirect Cost
Name
University of Maryland College Park
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
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Vega, Luis A; Valdes, Kayla M; Sundar, Ganesh S et al. (2017) The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes. Infect Immun 85:
Sundar, Ganesh S; Islam, Emrul; Gera, Kanika et al. (2017) A PTS EII mutant library in Group A Streptococcus identifies a promiscuous man-family PTS transporter influencing SLS-mediated hemolysis. Mol Microbiol 103:518-533
Freiberg, Jeffrey A; Le Breton, Yoann; Tran, Bao Q et al. (2016) Global Analysis and Comparison of the Transcriptomes and Proteomes of Group A Streptococcus Biofilms. mSystems 1:
Valdes, Kayla M; Sundar, Ganesh S; Vega, Luis A et al. (2016) The fruRBA Operon Is Necessary for Group A Streptococcal Growth in Fructose and for Resistance to Neutrophil Killing during Growth in Whole Human Blood. Infect Immun 84:1016-31
van der Beek, Samantha L; Le Breton, Yoann; Ferenbach, Andrew T et al. (2015) GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP-4-dehydrorhamnose reductases (RmlD). Mol Microbiol 98:946-62
Le Breton, Yoann; Belew, Ashton T; Valdes, Kayla M et al. (2015) Essential Genes in the Core Genome of the Human Pathogen Streptococcus pyogenes. Sci Rep 5:9838
Freiberg, Jeffrey A; McIver, Kevin S; Shirtliff, Mark E (2014) In vivo expression of Streptococcus pyogenes immunogenic proteins during tibial foreign body infection. Infect Immun 82:3891-9
Sachla, Ankita J; Le Breton, Yoann; Akhter, Fahmina et al. (2014) The crimson conundrum: heme toxicity and tolerance in GAS. Front Cell Infect Microbiol 4:159
Baruch, Moshe; Belotserkovsky, Ilia; Hertzog, Baruch B et al. (2014) An extracellular bacterial pathogen modulates host metabolism to regulate its own sensing and proliferation. Cell 156:97-108

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