Group A Streptococcus (GAS) is a major human pathogen that causes a variety of diseases, including relatively mild pharyngitis and skin infection and severe invasive infections such as sepsis and necrotizing fasciitis. Unfortunately, there is no licensed GAS vaccine, and severe invasive infections are difficult to treat with conventional antibiotics. A fundamental understanding of GAS pathogenesis is essential to the development of novel strategies to prevent and treat infections caused by this organism. The goal of this project is to clarify the mechanism for evasion of innate immunity by GAS. Based upon our preliminary studies, we hypothesize that the secreted esterase of GAS (designated SsE) plays a critical role in the inhibition of early neutrophil recruitment by GAS, which then allows the systemic spread of GAS to cause severe disease like sepsis. We further hypothesize that SsE hydrolyzes the platelet-activating factor and acts in tandem with other factor(s) to impede neutrophil responses. We pursue the following specific aims: (1) Determine whether SsE is required for inhibition of early neutrophil recruitment by GAS;(2) Determine whether SsE mediates inhibition of early neutrophil infiltration via hydrolysis of platelet-activating factor;nd (3) Test whether streptolysin S is responsible for the late collapse of neutrophil responses during subcutaneous infection of a sse mutant of a hypervirulent serotype M3 strain. The proposed studies promote two advancements. First, they will increase our understanding of GAS pathogenesis and progression of invasive GAS infections. Second, as a result, they will identify targets for development of a broad, efficacious GAS vaccine and new therapies for prevention and treatment of GAS infections. Overall, this project has the potential to define a novel mechanism for evasion of innate immunity by GAS and to establish a paradigm for bacterial inhibition of neutrophil recruitment and function.

Public Health Relevance

Medical significance: Group A Streptococcus (GAS) is a major cause of acute pharyngitis and severe invasive infections in humans. Unfortunately, no licensed GAS vaccine is available, and severe invasive GAS infections, including necrotizing fasciitis, are difficult to treat with current antibiotics. Investigation of how GAS evades the innte immune system will advance the understanding of GAS pathogenesis and its interaction with the host. These studies have potential to identify targets for developing novel therapy and broad vaccine for treat and prevent GAS infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI095704-01A1
Application #
8297945
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
GU, Xin-Xing
Project Start
2012-02-03
Project End
2017-01-31
Budget Start
2012-02-03
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$354,967
Indirect Cost
$104,967
Name
Montana State University - Bozeman
Department
Microbiology/Immun/Virology
Type
Schools of Earth Sciences/Natur
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
Liu, Mengyao; Feng, Wenchao; Zhu, Hui et al. (2015) A Neutralizing Monoclonal IgG1 Antibody of Platelet-Activating Factor Acetylhydrolase SsE Protects Mice against Lethal Subcutaneous Group A Streptococcus Infection. Infect Immun 83:2796-805
Stetzner, Zachary W; Li, Dengfeng; Feng, Wenchao et al. (2015) Serotype M3 and M28 Group A Streptococci Have Distinct Capacities to Evade Neutrophil and TNF-α Responses and to Invade Soft Tissues. PLoS One 10:e0129417
Liu, Guanghui; Feng, Wenchao; Li, Dengfeng et al. (2015) The Mga Regulon but Not Deoxyribonuclease Sda1 of Invasive M1T1 Group A Streptococcus Contributes to In Vivo Selection of CovRS Mutations and Resistance to Innate Immune Killing Mechanisms. Infect Immun 83:4293-303
Li, Jinquan; Liu, Guanghui; Feng, Wenchao et al. (2014) Neutrophils select hypervirulent CovRS mutants of M1T1 group A Streptococcus during subcutaneous infection of mice. Infect Immun 82:1579-90
Zhu, Hui; Li, Dengfeng; Liu, Mengyao et al. (2014) Non-heme-binding domains and segments of the Staphylococcus aureus IsdB protein critically contribute to the kinetics and equilibrium of heme acquisition from methemoglobin. PLoS One 9:e100744
Fonner, Brittany A; Tripet, Brian P; Lui, Mengyao et al. (2014) ¹H, ¹³C, ¹⁵N backbone and side chain NMR resonance assignments of the N-terminal NEAr iron transporter domain 1 (NEAT 1) of the hemoglobin receptor IsdB of Staphylococcus aureus. Biomol NMR Assign 8:201-5
Fonner, Brittany A; Tripet, Brian P; Eilers, Brian J et al. (2014) Solution structure and molecular determinants of hemoglobin binding of the first NEAT domain of IsdB in Staphylococcus aureus. Biochemistry 53:3922-33
Cai, He; Grunwald, Eric W; Park, Sung Yong et al. (2013) Lipid oxidation in trout muscle is strongly inhibited by a protein that specifically binds hemin released from hemoglobin. J Agric Food Chem 61:4180-7
Ran, Yanchao; Malmirchegini, G Reza; Clubb, Robert T et al. (2013) Axial ligand replacement mechanism in heme transfer from streptococcal heme-binding protein Shp to HtsA of the HtsABC transporter. Biochemistry 52:6537-47
Li, Jinquan; Zhu, Hui; Feng, Wenchao et al. (2013) Regulation of inhibition of neutrophil infiltration by the two-component regulatory system CovRS in subcutaneous murine infection with group A streptococcus. Infect Immun 81:974-83

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