Folate-Modulated Virulence of Porphyromonas gingivalis

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Periodontal disease, one of the most common infections of humans, is driven by pathogens that influence the composition and trajectory of the oral polymicrobial community. These pathogens can take hold in an inhospitable environment and pave the way for other organism to colonize and grow. A key factor in allowing a pathogen to establish itself and colonize despite these odds is successfully regulating the expression of virulence factors while acquiring enough essential nutrition for replication and growth. One such essential nutrient is folate, which is classically linked to modulation of virulence in microbes. Although the literature has shown that limiting folate availability leads to decreased virulence in many microbes, however, we have found a clear exception to this rule in the periodontal pathogen P. gingivalis, an asaccharolytic organism that uses an amino-acid based metabolism. As a model for studying how folate availability regulates virulence in asaccharolytic pathogens, we are investigating how restricting the ability of P. gingivalis to produce folate regulates its expression of virulence factors. The objectives of this study are to: i) define the metabolic phenotype of P. gingivalis induced by folate deficiency; ii) determine how the metabolic phenotype of P. gingivalis is associated with the expression of virulence factors; and iii) characterize the host immune response to folate-deficient P. gingivalis. The completion of this study will provide critical insight into how limiting folate availability does not universally suppress the virulence of pathogens, but has the potential to result in enhanced virulence in asaccharolytic pathogens. We will also provide novel information on how the flux of metabolites in the folate and one-carbon metabolic pathways are associated with virulence in P. gingivalis and how this could apply to other organisms utilizing non-carbohydrate based metabolisms. Our overall long-term goal is to apply these findings to refine when it is appropriate to use antifolates to treat microbial infections and reduce overall harm caused to patients. Further, these findings will help narrow down alternative pathways to target treatments for infections caused by asaccharolytic pathogens.