Autolysin Regulatory Machinery of Streptococcus Mutans in Bacterial Survival and Biofilm Formation in Infective Endocarditis

Infective endocarditis (IE) is an infectious disease of the cardiovascular system, and carries a high recurrence and mortality rate. Viridans streptococci, commensals in the oral cavity, are also major opportunistic pathogens for IE. Our data previously demonstrated the importance of host factors, including the platelets and neutrophil extracellular traps (NETs), in the pathogenesis of IE (Jung CJ, et. al., J Infect Dis. 2012; 205:1066-75; Circulation. 2015; 131:571-81), but the bacterial virulence for causing IE remain unclear. Escaping immune surveillance and forming biofilm are two determining virulent factors for bacteria to cause systemic infectious disease, such as IE. Our previous report demonstrated that one plasma component, calcium ion, is a key host factor that could enhance bacterial survival in the circulation through increasing the maturation of AtlA (Jung CJ, et. al., Mol Microbiol. 2009; 74:888–902). In addition, knocking out of AtlA in Streptococcus mutans dramatically reduce bacterial ability to cause IE in the rat model, suggesting AtlA play important roles in the pathogenesis of IE. In addition to mediate bacterial survival in the circulation, AtlA, which encodes autolysin, controls the release of bacterial extracellular DNA, one of major component of bacterial biofilm matrix. Our preliminary data also showed that the AtlA-deficient mutant strain reduce abilities to release bacterial eDNA and to form the biofilm in vitro and in vivo. Although we have identified that a plasma component, calcium ion, controls the maturation and the function of AtlA in our previous study, the underlying mechanism is still unknown. In addition, our preliminary data shown that an AtlA homologous protein, Ahp, may play roles in the modulation of the function of AtlA and in the pathogenesis of IE. Therefore, in the project, we will investigate the underlying mechanism of the regulation of AtlA maturation, including identification the bacterial regulating machinery and the downstream bacterial proteins for sensing calcium ions and N-terminal processing of AtlA. In addition, the roles and mechanisms of Ahp in the regulation of the function of AtlA and bacterial virulence for causing IE will also be investigated. The specific aims of this three-year project will be: 1)、 Identification of the bacterial regulatory system and proteins responsible for sensing calcium ions and regulating AtlA maturation 2)、 Elucidation of the role and function of Ahp in the regulation of AtlA function and S. mutans virulence in the pathogenesis of IE 3)、 Investigation of the roles of the proteins involved in the N-terminal procession of AtlA in the pathogenesis of IE In this project, we will cooperate with Dr. Jeng-Wei Cheng, an expert in the Department of Cardiovascular surgery, National Taiwan University, for the in vivo model of experimental bacterial endocarditis. The results obtained from this project will not only provide important information to the pathogenesis of IE, but also can be transferred to the translation medicine for searching the effective therapeutic strategies or prognostic markers for the controlling of IE in clinic.