Streptococcus pyogenes (Spy; group A Streptococcus) is the most prolific pathogen in the number of distinct diseases it is responsible for. Most commonly Spy is a cause of childhood acute pharyngitis (strep throat), but it is also a top-10-pathogen in mortality that results in more than half a million deaths annually through invasive infections and immune diseases that include necrotizing fasciitis, toxic shock syndrome, and acute rheumatic fever. Despite their public health importance, the pathogenesis of these severe diseases is poorly understood, and they remain challenging to treat. Our long-term goal seeks to determine how Spy virulence factors contribute to the development of these more severe forms of disease so that effective therapeutic countermeasures can be developed. Our previous studies show that the streptococcal protease SpeB acts directly on the host cytokine pro-IL-1? to induce inflammatory pathology during invasive infection. We hypothesize that additional proteins targeted by SpeB, from both host and microbe, contribute to the proinflammatory responses we see during infection. In our preliminary data, we have characterized the biochemical activity of SpeB and identified two of its substrates that cooperatively lead to fundamental shifts in pathogenesis. In our first aim, we examine how SpeB regulates the activities of M protein, a pleiotropic virulence factor with numerous host targets. By eliminating domains specific for the binding of some host molecules or anchoring of M protein to the Spy surface, SpeB directly contributes to pathological complications of infection like glomerulonephritis and toxic shock syndrome. In our second aim, we define the molecular determinates of how SpeB blocks signaling by the CovR/CovS two-component regulator by targeting its agonist, the host defense peptide LL-37. This mechanism results in a positive-feedback loop for SpeB production and repression of capsule and other cell surface factors that alter antimicrobial resistance, detection by the host, and promotes inflammation and disease complications.
Both aims take advantage of new genetic and biochemical tools we developed for targeted control and specific detection of SpeB and its substrates. These innovations allow us for the first time to separate activities for these multifunctional proteins and examine in vivo dramatic switch in the virulence strategy of Spy regulated by SpeB. The expected contribution of the proposed research is an expanded understanding of how Spy pathogenesis is regulated that provides attractive therapeutic targets for the prevention and treatment of severe Spy disease and insights into orthologous systems of other pathogens highly relevant to the NIAID mission.

Public Health Relevance

Streptococcus pyogenes causes many diseases and is a leader of infectious morbidity and mortality responsible for >500,000 annual deaths. This project how one of its proteases regulates bacterial virulence mechanisms that lead to toxic shock syndrome and invasive infections like necrotizing fasciitis. Advancing our understanding of this process will give new therapeutic strategies to treat antibiotic-refectory severe disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI153071-01A1
Application #
10209054
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
GU, Xin-Xing
Project Start
2021-01-15
Project End
2025-12-31
Budget Start
2021-01-15
Budget End
2021-12-31
Support Year
1
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322