Dental caries is a multi-faceted disease caused by interactions of cariogenic bacteria present in oral biofilms with salivary components and dietary carbohydrates. Despite significant advances in our understanding of the etiology and pathogenesis of this disease, dental caries remains the most prevalent and costly biofilm-associated infection worldwide. Among the hundreds of bacterial species residing in the oral biofilm, Streptococcus mutans has long been known as a primary cariogenic agent by its ability to drive the ecological transition of the biofilm population from non-cariogenic to cariogenic. The capacities to synthesize a thick extracellular polysaccharide matrix from sucrose, to generate copious amounts of lactic acid through carbohydrate fermentation, and to rapidly adapt to environmental stresses are the key virulence attributes of S. mutans. Although acidogenicity and aciduricity are well-established stress factors involved in virulence, the ability to cope with endogenous and exogenous reactive oxygen species is also viewed as an important attribute in the pathophysiology of S. mutans. This competing renewal has been set forth to study, at the molecular and physiologic levels, the Spx oxidative stress regulators of S. mutans. The Spx protein is highly conserved among Firmicutes and elegant studies with the Gram-positive paradigm Bacillus subtilis have shown that it exerts positive control over oxidative stress genes through direct interactions with the RNA polymerase and the promoter DNA region. Our work in the previous funding cycle identified two bona fide Spx paralogs (SpxA1 and SpxA2) in the genome of S. mutans, and showed that stress tolerances and virulence are significantly impaired in strains lacking one or both spx genes. Following our initial study, evidence of two Spx regulatory systems emerged in other bacteria and the importance of Spx regulation to virulence has been expanded to other streptococcal species. Although the spx gene has been well characterized in B. subtilis, the interplay among two Spx paralogs and the scope of Spx regulation in pathogenic organisms such as S. mutans are not well understood. The goals of this project are to understand the hierarchical relationship of the two Spx paralogs and uncover novel, Spx regulated, antioxidant strategies in S. mutans. To accomplish these goals, we propose three specific aims.
In Aim 1, we will unravel the regulatory network controlling cellular abundance of the Spx proteins. In the second aim, we will determine, at the molecular level, the regulatory capacities of each Spx protein in relation to oxidative stress gene activation. In the third aim, we will take advantage of the prominent role of SpxA1 in activation of oxidative stress responses to uncover how S. mutans respond to peroxide stress at the metabolic level and to identify novel antioxidant pathways. The successful completion of this project will provide new leads on bacterial processes that can be exploited for new therapeutic and preventive strategies.
Dental caries is one of the most common infectious diseases afflicting humans and it originates from interactions of specific bacteria with proteins present in saliva and dietary sugars. While a common resident of the oral cavity in small numbers, the outgrowth of a bacterium called Streptococcus mutans in dental plaque has been consistently linked to caries onset. The goal of this study is to investigate the molecular mechanisms used by S. mutans to outcompete non-cariogenic bacteria in the oral cavity and cause dental caries. These studies can facilitate the development of new products to prevent and treat dental caries as well as other types of bacterial infections caused by related streptococcal bacteria.
|Ganguly, Tridib; Kajfasz, Jessica K; Miller, James H et al. (2018) Disruption of a Novel Iron Transport System Reverses Oxidative Stress Phenotypes of a dpr Mutant Strain of Streptococcus mutans. J Bacteriol 200:|
|Galvão, L C C; Rosalen, P L; Rivera-Ramos, I et al. (2017) Inactivation of the spxA1 or spxA2 gene of Streptococcus mutans decreases virulence in the rat caries model. Mol Oral Microbiol 32:142-153|
|Kajfasz, Jessica K; Ganguly, Tridib; Hardin, Emily L et al. (2017) Transcriptome responses of Streptococcus mutans to peroxide stress: identification of novel antioxidant pathways regulated by Spx. Sci Rep 7:16018|
|Hwang, Geelsu; Liu, Yuan; Kim, Dongyeop et al. (2016) Simultaneous spatiotemporal mapping of in situ pH and bacterial activity within an intact 3D microcolony structure. Sci Rep 6:32841|
|Papadimitriou, Konstantinos; Alegría, Ángel; Bron, Peter A et al. (2016) Stress Physiology of Lactic Acid Bacteria. Microbiol Mol Biol Rev 80:837-90|
|Baker, J L; Abranches, J; Faustoferri, R C et al. (2015) Transcriptional profile of glucose-shocked and acid-adapted strains of Streptococcus mutans. Mol Oral Microbiol 30:496-517|
|Kajfasz, Jessica K; Rivera-Ramos, Isamar; Scott-Anne, Kathleen et al. (2015) Transcription of Oxidative Stress Genes Is Directly Activated by SpxA1 and, to a Lesser Extent, by SpxA2 in Streptococcus mutans. J Bacteriol 197:2160-2170|
|Galvão, Lívia C C; Miller, James H; Kajfasz, Jessica K et al. (2015) Transcriptional and Phenotypic Characterization of Novel Spx-Regulated Genes in Streptococcus mutans. PLoS One 10:e0124969|
|Baker, J L; Derr, A M; Karuppaiah, K et al. (2014) Streptococcus mutans NADH oxidase lies at the intersection of overlapping regulons controlled by oxygen and NAD+ levels. J Bacteriol 196:2166-77|
|Lemos, José A; Quivey Jr, Robert G; Koo, Hyun et al. (2013) Streptococcus mutans: a new Gram-positive paradigm? Microbiology 159:436-45|
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