The high prevalence of cardiovascular diseases (CVD) in the United States is a long standing problem affecting over 82 million of American adults. In the cases of multifactorial diseases such as atherosclerosis and infective endocarditis (IE), persistent and/or recurrent infection and chronic inflammation are believed to be important risk factors. Genomic amplifications of bacterial DNA from heart valve lesions and atheromatous plaque indicate that the dental pathogen Streptococcus mutans is a prevalent organism at these sites. Invasive strains of S. mutans have been associated with higher virulence and increased inflammation suggesting a novel and poorly understood role of this pathogen in CVD. Thus, analysis on the frequency of invasive S. mutans strains in CVD specimens (specifically atherosclerosis and IE), and the determination of host immune responses to S. mutans infection can provide a more clear picture of the role of S. mutans in CVD. In previous studies, we have described that expression of a collagen binding protein, Cnm, by S. mutans provides it with ability to bind to collagen and laminin, invade human coronary endothelial cells and more efficiently kill the larvae of Galleria mellonella. This invasive property appears to contribute to increased inflammation through the production of pro-inflammatory chemokines and is thought to play a role in antibiotic and immune evasion. Therefore, Cnm could contribute to persistent infections and chronic inflammation through the invasion of non-professional phagocytic cells and evasion of antibiotic treatment and immune surveillance. Additionally, the cnm gene is found at a significantly higher frequency in S. mutans strains belonging to serotypes e, f and k, which are highly associated with extra-oral infections, when compared to serotype c strains, which constitute 70% of oral isolates. Our current hypothesis is that Cnm-mediated ability to bind and invade human tissues allows S. mutans to escape therapeutic challenges and evade host immune responses;therefore associating Cnm-expressing S. mutans with persistent and chronic inflammatory CVD. In this application, we propose to (Aim 1) determine the ability of various S. mutans strains (invasive vs. non-invasive) to induce an altered innate immune response and to invade non-endothelial cell lines, and to (Aim 2) determine the frequency of S. mutans and of Cnm in infected heart valves and atheromas. Successful completion of these aims will establish a clear link between S. mutans persistent infection and chronic inflammation, and provide much-needed epidemiological insight of S. mutans association with CVD in the US.
The goal of this project is to use in vitro approaches to evaluate host immune responses towards highly pathogenic strains of Streptococcus mutans and to determine the prevalence of this pathogen in cardiovascular vegetations and atheromas. A better understanding of how oral bacteria contribute to cardiovascular disease and systemic inflammation will reveal new avenues of research for discovery of therapeutic strategies.