Streptococcus pyogenes (Group A Streptococcus, GAS) is an important human pathogen that causes numerous diseases ranging from minor skin and throat infections such as impetigo and pharyngitis to life-threatening invasive infections such as streptococcal toxic syndrome and necrotizing fasciitis. Worldwide GAS infections account for more than 600 million cases of pharyngitis and more than 650,000 cases of invasive disease annually. Since the late 1980s, there has been a worldwide increase in invasive GAS disease. Although the pathogen is susceptible to antibiotic therapy, severe invasive GAS infections are often difficult to treat. Hyaluronic acid (HA) capsule is considered one of the major determinants of GAS virulence. Highly encapsulated GAS strains are associated with both invasive infections and outbreaks of acute rheumatic fever. GAS mutants lacking capsule are sensitive to neutrophil killing and have reduced virulence in murine model of GAS infection. In addition to its role in bacterial resistance to host defense attack, HA capsule mediates adherence and promotes GAS colonization of the pharynx. Capsule expression requires effective and sensitive control mechanisms to avoid excessive capsule overproduction. In the current model, CovR binds to the promoter region of the has capsule gene operon comprised of hasABC genes and represses its transcription. However the details of this mechanism are mostly unclear. The primary objective of the proposed research is to understand the molecular mechanisms of HA capsule regulation. In our preliminary studies we identified a novel regulatory noncoding region that controls capsule operon transcription. We confirmed that the region is physiologically significant and is important for full virulence in a mouse model of GAS invasive disease. Moreover, we found that the region is under strong selective pressure resulting in accumulation of spontaneous mutations in GAS clinical strains. We propose to define this novel capsule regulation mechanism using advanced genetic and biochemical techniques. The outcomes of this research are expected to have a positive impact on the development of diagnostic analysis during outbreaks of GAS infection and highly targeted therapeutics to control the invasive GAS disease.

Public Health Relevance

The proposed research investigates the mechanism of regulation of hyaluronic acid capsule biosynthesis in the important human pathogen, Streptococcus pyogenes. Hyaluronic acid capsule is one of the major determinants of S. pyogenes virulence. The expected findings will guide a development of diagnostic analysis during outbreaks of infections and novel therapeutics to control S. pyogenes invasive disease.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI113253-01
Application #
8765760
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
GU, Xin-Xing
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Lexington
State
KY
Country
United States
Zip Code
40506