Group A Streptococcus (GAS) is an exclusive human pathogen that causes a wide spectrum of disease conditions. Disease burden caused by GAS infections is significant as the invasive GAS infections alone account for approximately 500,000 deaths worldwide every year. Given the difficulties in treating the invasive infections, rise in GA invasive disease outbreaks, and lack of effective prophylactic measures, it is critical to investigate the virulence regulatory mechanisms and identify novel antimicrobial targets. Secreted cysteine protease, SpeB, is produced abundantly during infection and is critical for the pathogenesis of GAS invasive infections. GAS global transcription regulator, RopB, controls the expression of ~ 25% of GAS genome including speB in a growth phase- dependent manner. Although RopB is essential for the transcription regulation, it requires growth- phase-specific input signals to mediate gene regulation. Using a multidisciplinary approach, we recently demonstrated that RopB uses GAS-encoded secreted peptides as intercellular signals to control virulence regulation in concert with cell density. Our studies revealed that peptide signals originating from the secretion signal sequence of Vfr inhibits RopB-dependent virulence gene expression during low cell density. Although our preliminary data indicate that high cell density- specific activation peptide signal(s) activates RopB-mediated gene regulation, both the genetic and biochemical identity of the peptide signals remain unknown. Using a combination of genetic, biochemical, biophysical approach, and animal models of infection, we will study three major aspects of this signaling circuit namely, signal generation, signal sensing, and signal transduction. Data generated from this study will elucidate the key components of an important virulence regulatory pathway and may elucidate novel molecular targets for the development of antimicrobials to treat GAS invasive infections.

Public Health Relevance

Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is a strict human pathogen that causes an estimated ~ 600 million cases of strep throat and 500,000 cases of invasive disease-related deaths worldwide. This research plan will identify novel peptide signals that control bacterial toxin production in concert with population density. Characterization of the signaling mechanism will enhance our understanding of how GAS causes disease and may pave the foundation for novel therapeutic strategies against GAS infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI109096-03
Application #
9206980
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
GU, Xin-Xing
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$398,750
Indirect Cost
$148,750
Name
Methodist Hospital Research Institute
Department
Type
Other Domestic Non-Profits
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030
Makthal, Nishanth; Do, Hackwon; VanderWal, Arica R et al. (2018) Signaling by a Conserved Quorum Sensing Pathway Contributes to Growth Ex Vivo and Oropharyngeal Colonization of Human Pathogen Group A Streptococcus. Infect Immun 86:
Makthal, Nishanth; Kumaraswami, Muthiah (2017) Zinc'ing it out: zinc homeostasis mechanisms and their impact on the pathogenesis of human pathogen group A streptococcus. Metallomics 9:1693-1702
Makthal, Nishanth; Nguyen, Kimberly; Do, Hackwon et al. (2017) A Critical Role of Zinc Importer AdcABC in Group A Streptococcus-Host Interactions During Infection and Its Implications for Vaccine Development. EBioMedicine 21:131-141
Do, Hackwon; Makthal, Nishanth; VanderWal, Arica R et al. (2017) Leaderless secreted peptide signaling molecule alters global gene expression and increases virulence of a human bacterial pathogen. Proc Natl Acad Sci U S A 114:E8498-E8507
VanderWal, Arica R; Makthal, Nishanth; Pinochet-Barros, Azul et al. (2017) Iron Efflux by PmtA Is Critical for Oxidative Stress Resistance and Contributes Significantly to Group A Streptococcus Virulence. Infect Immun 85:
Do, Hackwon; Kumaraswami, Muthiah (2016) Structural Mechanisms of Peptide Recognition and Allosteric Modulation of Gene Regulation by the RRNPP Family of Quorum-Sensing Regulators. J Mol Biol 428:2793-804
Makthal, Nishanth; Gavagan, Maire; Do, Hackwon et al. (2016) Structural and functional analysis of RopB: a major virulence regulator in Streptococcus pyogenes. Mol Microbiol 99:1119-33
Sanson, Misu; Makthal, Nishanth; Gavagan, Maire et al. (2015) Phosphorylation events in the multiple gene regulator of group A Streptococcus significantly influence global gene expression and virulence. Infect Immun 83:2382-95
Olsen, Randall J; Laucirica, Daniel R; Watkins, M Ebru et al. (2012) Polymorphisms in regulator of protease B (RopB) alter disease phenotype and strain virulence of serotype M3 group A Streptococcus. J Infect Dis 205:1719-29