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.
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.
|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|
|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|
|Cody, William L; Wilson, James W; Hendrixson, David R et al. (2008) Skim milk enhances the preservation of thawed -80 degrees C bacterial stocks. J Microbiol Methods 75:135-8|
|Ribardo, Deborah A; McIver, Kevin S (2006) Defining the Mga regulon: Comparative transcriptome analysis reveals both direct and indirect regulation by Mga in the group A streptococcus. Mol Microbiol 62:491-508|
|Vahling, Cheryl M; McIver, Kevin S (2006) Domains required for transcriptional activation show conservation in the mga family of virulence gene regulators. J Bacteriol 188:863-73|
|Vahling, Cheryl M; McIver, Kevin S (2005) Identification of residues responsible for the defective virulence gene regulator Mga produced by a natural mutant of Streptococcus pyogenes. J Bacteriol 187:5955-66|
|Ribardo, Deborah A; Lambert, Thomas J; McIver, Kevin S (2004) Role of Streptococcus pyogenes two-component response regulators in the temporal control of Mga and the Mga-regulated virulence gene emm. Infect Immun 72:3668-73|
Showing the most recent 10 out of 12 publications