Bacterial pathogens must adapt to available nutrients in their host, so they have linked metabolism with virulence. We want to understand the mechanisms by which G+ pathogens regulate virulence in response to available carbohydrates. GAS is a significant pathogen causing an array of diseases and depends upon sugar uptake for host survival. The PTS is a conserved phosphorelay coupling sugar transport and signal transduction.The Mga regulator influences both virulence and sugar utilization genes in GAS. We've shown that Mga is phosphorylated within PTS regulatory domains (PRD) that alter Mga activity and virulence in GAS. Furthermore, homologous regulators are found in GAS and other pathogenic streptococci. We propose that Mga represents a family of PRD-containing virulence regulators (PCVR) that allows sugar metabolism to influence the disease process. This renewal will continue our studies on Mga as the archetype PCVR, while expanding our scope to include potential PCVR from pathogenic streptococci. We propose the following aims: 1) Further define functional domains of Mga and establish their conservation in other PCVRs from pathogenic streptococci;2) Delineate the role of PTS components and sugars for signaling through Mga and potentially other RALPs in GAS;3) Map the genome-wide genetic interactions of Mga in GAS using Tn-seq;4) Examine the impact of PTS signaling on Mga and potentially RALPs during GAS infection. Advancing our understanding of PCVRs has potential for broad impact in the field of G+ bacterial pathogenesis and will hopefully lead to novel strategies to treat severe infections caused by these pathogens.

Public Health Relevance

Bacterial pathogens must adapt to available nutrients in their host, so they have linked metabolism with virulence. The Mga virulence regulator of the group A streptococcus (GAS) represents a family of PRD- containing virulence regulators (PCVR) that allows sugar metabolism to influence the disease process. This renewal will continue our studies on Mga as the archetype PCVR, while expanding our scope to include potential PCVR from pathogenic streptococci.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047928-13
Application #
8604348
Study Section
Special Emphasis Panel (ZRG1-IDM-A (02))
Program Officer
GU, Xin-Xing
Project Start
2000-07-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
13
Fiscal Year
2014
Total Cost
$329,346
Indirect Cost
$104,346
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
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
Sundar, Ganesh S; Islam, Emrul; Gera, Kanika et al. (2016) A PTS EII mutant library in Group A Streptococcus identifies a promiscuous man-family PTS transporter influencing SLS-mediated hemolysis. Mol Microbiol :
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
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
Gera, Kanika; Le, Tuquynh; Jamin, Rebecca et al. (2014) The phosphoenolpyruvate phosphotransferase system in group A Streptococcus acts to reduce streptolysin S activity and lesion severity during soft tissue infection. Infect Immun 82:1192-204
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
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
Le Breton, Yoann; Mistry, Pragnesh; Valdes, Kayla M et al. (2013) Genome-wide identification of genes required for fitness of group A Streptococcus in human blood. Infect Immun 81:862-75
Hondorp, Elise R; Hou, Sherry C; Hause, Lara L et al. (2013) PTS phosphorylation of Mga modulates regulon expression and virulence in the group A streptococcus. Mol Microbiol 88:1176-93

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