The pathogenic persona of community-associated oral streptococci

Abstract

The mitis group streptococci (MGS) are widespread in the oral cavity and are traditionally associated with oral health. However, these organisms have many attributes that contribute to the development of pathogenic oral communities. MGS adhere rapidly to saliva-coated tooth surfaces, thereby providing an attachment substratum for more overtly pathogenic organisms such as Porphyromonas gingivalis, and the two species assemble into heterotypic communities. Close physical association facilitates physiologic support, and pathogens such as Aggregatibacter actinomycetemcomitans display resource partitioning to favour carbon sources generated by streptococcal metabolism. MGS exchange information with community members through a number of interspecies signalling systems including AI-2 and contact dependent mechanisms. Signal transduction systems induced in P. gingivalis are based on protein dephosphorylation mediated by the tyrosine phosphatase Ltp1, and converge on a LuxR-family transcriptional regulator, CdhR. Phenotypic responses in P. gingivalis include regulation of hemin uptake systems and gingipain activity, processes that are intimately linked to the virulence of the organism. Furthermore, communities of S. gordonii with P. gingivalis or with A. actinomycetemcomitans are more pathogenic in animal models than the constituent species alone. We propose that MGS should be considered accessory pathogens, organisms whose pathogenic potential only becomes evident in the context of a heterotypic microbial community.

Figure 1

Structures required for the maintenance and stabilization of P. gingivalis-S. gordonii coadhesion. Center panel depicts the FimA-GAPDH and Mfa-Ssp adhesion-receptor pairs on the surfaces of P. gingivalis and S. gordonii. The left panel shows the interacting domains (lighter colour) of the FimA and GAPDH proteins with the amino acid (aa) residues indicated. The upper right panel shows the domain structure of the SspB protein and the aa residues involved in recognition of Mfa. LP: leader peptide; A: Ala-rich repeats; V: variable region; P: Pro-rich repeats; BAR: Mfa interacting domain; CWA: cell-wall anchor. BAR spans aa residues 1167-1193, and the EAAP, KKVQDLLKK, and NITVK sequences are involved in Mfa recognition. The lower right panel shows the structure of the SspB C-terminal region with the BAR handle region BAR handle stabilized by a calcium ion, and coordinated by three main chain and two side chain oxygen atoms and a water molecule. Crystal structure reproduced with permission from Forsgren et al. (2010).

Figure 2

Schematic depiction of metabolite sensing by A. actinomycetemcomitans during growth with S. gordonii. Lactate produced by S. gordonii is transported into A. actinomycetemcomitans by the proton-driven lactate permease (LctP). Lactate dehydrogenase (LctD) converts lactate into pyruvate which inhibits autophosphorylation of E1, and thus decreases uptake of PTS carbohydrates such as glucose. Preferential utilization of lactate increases the competitive fitness of A. actinomycetemcomitans in the presence of organisms that can metabolize glucose more efficiently. S. gordonii derived hydrogen peroxide stimulates activation of the A. actinomycetemcomitans OxyR regulator, thereby increasing transcription of both apiA and katA. Elevated expression of ApiA leads to enhanced complement resistance and potentially higher levels of intracellular invasion and proinflammatory cytokine induction. Increased levels of KatA (catalase) will consume excess hydrogen peroxide, produced by both S. gordonii and neutrophils, thereby protecting A. actinomycetemcomitans from oxidative damage. Model compiled from Brown and Whiteley (2007), and Ramsey and Whiteley (2009).

Figure 3

Model of the interconnected networks of regulatory circuitry governing the heterotypic community development between P. gingivalis and S. gordonii. Convergence of the Ltp1 signaling system on CdhR results in the cumulative effect of constraining P. gingivalis-S. gordonii community formation. Interaction of Mfa fimbriae with S. gordonii initiates a signaling event that is transduced through Ltp1 and propagated throughout the community via a cascade of phosphorylation/dephosphorylation events. Ltp1 activity results in downregulation of exopolysaccharide production and dephosphorylation of the gingipain proteases Kgp and Rgp. Ltp1 activity indirectly upregulates CdhR expression, and CdhR represses transcription of luxS and mfa operons in P. gingivalis. Lower AI-2 levels sensed by additional P. gingivalis cells cause upregulation of CdhR and facilitate propagation of the original streptococcal-derived signal throughout the P. gingivalis-S. gordonii community.