Group A Streptococcus (GAS) is a major human pathogen that causes a variety of diseases, including relatively mild pharyngitis and severe invasive infections, such as necrotizing fasciitis. Unfortunately, there is no licensed GAS vaccine, and severe invasive infections are difficult to treat with conventional antibiotics. The goals of this project are to develop a candidate vaccine for GAS diseases and protective monoclonal antibodies for future development of immunotherapy to treat severe invasive infections. The endeavors of several decades made by academic and industrial communities have demonstrated that any of the vaccine candidates tested yet is not sufficient for a broad, efficacious GAS vaccine due to sequence variation or limited capacity of protection of protective antigens. As a new strategy to tackle the problems in development of GAS vaccine and treatment, we will target both the secreted esterase of GAS (designated SsE) and streptolysin S (SLS). The sse gene is required for the virulence and dissemination of a hypervirulent serotype M1 strain in a mouse model of necrotizing fasciitis. Active and passive immunizations with SsE significantly protects mice against subcutaneous GAS infection and bacterial spreading in the subcutis. Our preliminary data shows that the sse gene is also required for GAS virulence and throat colonization in intranasal infection of mice. The SsE gene is required for inhibition of neutrophil recruitment. These findings indicate that SsE is involved in the innate immune evasion by GAS and is a critical virulence factor and protective antigen. However, SsE is not a sufficiently protective antigen for some clinical strains. Our preliminary data suggest that SsE and SLS function in tandem to block neutrophil functions in subcutaneous infection of mice with a hypervirulent serotype M3 strain and that SLS is critical for GAS virulence and throat colonization. It is known that antibodies can be raised against the C-terminal fragment of SagA, the peptide component of SLS, and neutralize the hemolytic activity of SLS. We hypothesize that we can develop an efficacious, broad GAS vaccine based on SsE and SagA. We also hypothesize that monoclonal antibodies (mAbs) neutralizing the activity of SsE and SLS can be used to treat severe GAS infections. We will test the efficacy of SsE and SagA -based vaccine formulations against GAS infections using mouse models of intranasal and subcutaneous infections in Aim 1.
In Aim 2, we will generate SsE- and SagA-specific inhibitory mAbs and test whether inhibitory mAbs protect mice against subcutaneous GAS infection in passive immunization. The project has the potential to lead to the development of a broad vaccine against GAS diseases and an antibody therapy to treat severe GAS infections.
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 are difficult to treat. This project will test the potential of two virulence factors as the targets for the development of a ne GAS vaccine and generation of protective monoclonal antibodies. If realized, the findings may lead to the further development of a broad, efficacious vaccine against GAS diseases and an immunotherapy against severe GAS infections.
|Feng, Wenchao; Minor, Dylan; Liu, Mengyao et al. (2017) Null Mutations of Group A Streptococcus Orphan Kinase RocA: Selection in Mouse Infection and Comparison with CovS Mutations in Alteration of In Vitro and In Vivo Protease SpeB Expression and Virulence. Infect Immun 85:|
|Feng, Wenchao; Liu, Mengyao; Chen, Daniel G et al. (2016) Contemporary Pharyngeal and Invasive emm1 and Invasive emm12 Group A Streptococcus Isolates Exhibit Similar In Vivo Selection for CovRS Mutants in Mice. PLoS One 11:e0162742|
|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-? 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|
|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|
|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|
|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|
|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|
|Liu, Guanghui; Liu, Mengyao; Xie, Gang et al. (2013) Characterization of streptococcal platelet-activating factor acetylhydrolase variants that are involved in innate immune evasion. Infect Immun 81:3128-38|
|Zhou, Yang; Hanks, Tracey S; Feng, Wenchao et al. (2013) The sagA/pel locus does not regulate the expression of the M protein of the M1T1 lineage of group A Streptococcus. Virulence 4:698-706|
Showing the most recent 10 out of 12 publications