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Dental caries is a globally prevalent condition that occurs when pathogenic species, including Streptococcus mutans and Candida albicans , outcompete beneficial species, such as Streptococcus gordonii , in the dental biofilm. Fluoride is routinely used in oral hygiene to prevent dental caries. Fluoride also has antimicrobial properties, although most microbes possess fluoride exporters to resist its toxicity. This work shows that sensitization of cariogenic species S. mutans and C. albicans to fluoride by genetic knockout of fluoride exporters alters the microbial composition and pathogenic properties of dental biofilms. These results suggest that the development of drugs that inhibit fluoride exporters could potentiate the anticaries effect of fluoride in over-the-counter products like toothpaste and mouth rinses. This is a novel strategy to treat dental caries.

Our research explores the mechanisms of bacterial adhesion within the dental plaque, focusing on Veillonella parvula , a key player in the oral microbiome. Dependent on lactate from streptococci, V. parvula plays a crucial bridging role in the formation of dental biofilms by co-aggregating with other bacteria. Despite its importance, the understanding of the underlying mechanisms of co-aggregation remains limited. Our study shows that V. parvula uses different trimeric autotransporters to adhere to oral Streptococci and Actinomyces. We additionally identify a novel adhesin from S. gordonii , VisA (SGO_2004) facilitating this interaction. We found that although co-aggregation does not affect cell-cell communication, it is critical for biofilm structure and species distribution. This research opens up new avenues for exploring microbial interactions in dental health and diseases.

Many human infections are polymicrobial in origin, and interactions among community inhabitants shape colonization patterns and pathogenic potential 1 . Periodontitis, which is the sixth most prevalent infectious disease worldwide 2 , ensues from the action of dysbiotic polymicrobial communities 3 . The keystone pathogen Porphyromonas gingivalis and the accessory pathogen Streptococcus gordonii interact to form communities in vitro and exhibit increased fitness in vivo 3 , 4 . The mechanistic basis of this polymicrobial synergy, however, has not been fully elucidated. Here we show that streptococcal 4-aminobenzoate/ para -amino benzoic acid ( p ABA) is required for maximal accumulation of P. gingivalis in dual-species communities. Metabolomic and proteomic data showed that exogenous p ABA is used for folate biosynthesis, and leads to decreased stress and elevated expression of fimbrial adhesins. Moreover, p ABA increased the colonization and survival of P. gingivalis in a murine oral infection model. However, p ABA also caused a reduction in virulence in vivo and suppressed extracellular polysaccharide production by P. gingivalis . Collectively, these data reveal a multidimensional aspect to P. gingivalis – S. gordonii interactions and establish p ABA as a critical cue produced by a partner species that enhances the fitness of P. gingivalis while diminishing its virulence. Streptococcal para-amino benzoic acid enhances Porphyromonas gingivalis colonization while reducing virulence during polymicrobial oral infection.

Infection is one of the most prevalent causes for dental implant failure. We have developed a novel antimicrobial peptide coating on titanium by immobilizing the antimicrobial peptide GL13K. GL13K was developed from the human salivary protein BPIFA2. The peptide exhibited MIC of 8 µg/ml against planktonic Pseudonomas aeruginosa and their biofilms were reduced by three orders of magnitude with 100 µg/ml GL13K. This peptide concentration also killed 100% of Streptococcus gordonii. At 1 mg/ml, GL13K caused less than 10% lysis of human red blood cells, suggesting low toxicity to mammalian cells. Our GL13K coating has also previously showed bactericidal effect and inhibition of biofilm growth against peri-implantitis related pathogens, such as Porphyromonas gingivalis. The GL13K coating was cytocompatible with human fibroblasts and osteoblasts. However, the bioactivity of antimicrobial coatings has been commonly tested under (quasi)static culture conditions that are far from simulating conditions for biofilm formation and growth in the oral cavity. Oral salivary flow over a coating is persistent, applies continuous shear forces, and supplies sustained nutrition to bacteria. This accelerates bacteria metabolism and biofilm growth. In this work, the antimicrobial effect of the coating was tested against Streptococcus gordonii, a primary colonizer that provides attachment for the biofilm accretion by P. gingivalis, using a drip-flow biofilm bioreactor with media flow rates simulating salivary flow. The GL13K peptide coatings killed bacteria and prevented formation and growth of S. gordonii biofilms in the drip-flow bioreactor and under regular mild-agitation conditions. Surprisingly the interaction of the bacteria with the GL13K peptide coatings ruptured the cell wall at their septum or polar areas leaving empty shell-like structures or exposed protoplasts. The cell wall rupture was not detected under regular culture conditions, suggesting that cell wall rupture induced by GL13K peptides also requires media flow and possible attendant biological sequelae of the conditions in the bioreactor.

Type VII secretion system (T7SS) substrate EsxA contributes to the pathogenesis of several Gram-positive bacteria, but its role in viridans streptococci-induced infective endocarditis (IE) remains unclear. Genomic analysis of the Streptococcus gordonii DL1 strain identified a genetic locus encoding five T7SSb core machinery proteins (EsaA, EssA, EsaB, EssB, and EssC) and one substrate, EsxA. T7SSb mediates EsxA secretion, as evidenced by reduced secretion in the essC -deleted mutant and restoration upon complementation. In a rat model of IE, the esxA -deficient strain shows lower survival in circulation and reduced formation of vegetation, suggesting a role for EsxA in IE pathogenesis. Using a transwell system, molecules secreted from wild-type S. gordonii DL1 can induce the release of neutrophil extracellular traps (NETs) by neutrophils, and this activity is lost in the esxA -deficient strain. In addition, recombinant EsxA can dose-dependently induce NET formation, confirming a role for secreted EsxA in the induction of NET formation. Consistently, reduced and restored NET formation is observed in vivo in vegetations caused by esxA -deficient and complemented strains, respectively. Together, these data indicate that EsxA secretion mediated by T7SSb induces NET formation that contributes to bacterial survival in the circulation and vegetation formation in S. gordonii -induced IE.

Many oral bacteria form macroscopic clumps known as coaggregates when mixed with a different species. It is thought that these cell-cell interactions are critical for the formation of mixed-species biofilms such as dental plaque. Here, we assessed the impact of coaggregation between two key initial colonizers of dental plaque, Streptococcus gordonii and Veillonella parvula , on gene expression in each partner. These species were shown to coaggregate in buffer or human saliva. To monitor gene regulation, coaggregates were formed in human saliva and, after 30 minutes, whole-transcriptomes were extracted for sequencing and Dual RNA-Seq analysis. In total, 272 genes were regulated in V. parvula , including 39 genes in oxidoreductase processes. In S. gordonii , there was a high degree of inter-sample variation. Nevertheless, 69 genes were identified as potentially regulated by coaggregation, including two phosphotransferase system transporters and several other genes involved in carbohydrate metabolism. Overall, these data indicate that responses of V. parvula to coaggregation with S. gordonii are dominated by oxidative stress-related processes, whereas S. gordonii responses are more focussed on carbohydrate metabolism. We hypothesize that these responses may reflect changes in the local microenvironment in biofilms when S. gordonii or V. parvula immigrate into the system.

Streptococcus gordonii and Streptococcus sanguinis belong to the Mitis group streptococci, which mostly are commensals in the human oral cavity. Though they are oral commensals, they can escape their niche and cause infective endocarditis, a severe infection with high mortality. Several virulence factors important for the development of infective endocarditis have been described in these two species. However, the background for how the commensal bacteria, in some cases, become pathogenic is still not known. To gain a greater understanding of the mechanisms of the pathogenic potential, we performed a comparative analysis of 38 blood culture strains, S . sanguinis ( n  = 20) and S . gordonii ( n  = 18) from patients with verified infective endocarditis, along with 21 publicly available oral isolates from healthy individuals, S . sanguinis ( n  = 12) and S . gordonii (n  = 9). Using whole genome sequencing data of the 59 streptococci genomes, functional profiles were constructed, using protein domain predictions based on the translated genes. These functional profiles were used for clustering, phylogenetics and machine learning. A clear separation could be made between the two species. No clear differences between oral isolates and clinical infective endocarditis isolates were found in any of the 675 translated core-genes. Additionally, random forest-based machine learning and clustering of the pan-genome data as well as amino acid variations in the core-genome could not separate the clinical and oral isolates. A total of 151 different virulence genes was identified in the 59 genomes. Among these homologs of genes important for adhesion and evasion of the immune system were found in all of the strains. Based on the functional profiles and virulence gene content of the genomes, we believe that all analysed strains had the ability to become pathogenic.

is an unusual diderm firmicute that plays a central role in the formation of dental biofilm formation through coaggregation with many other oral bacteria. However, the molecular interactions leading to oral biofilm formation are largely unknown. In a recent study (L. Dorison, N. Béchon, C. Martin-Gallausiaux, S. Chamorro-Rodriguez, et al., mBio 15:e02171-24, 2024, https://doi.org/10.1128/mbio.02171-24), coaggregation by was shown to be mediated by trimeric autotransporter adhesins (TAAs), which are large, fibrous surface proteins widespread in Gram-negative bacteria. Importantly, this study identified the binding partner protein on a coaggregating bacterium, , which the authors called VisA. This finding is the first time a TAA mediating coaggregation with a different type of protein has been established and suggests that specifically interacting protein partners may have coevolved multiple times to allow complex biofilm formation, as exemplified by the development of dental plaque. Understanding these interactions might lead to innovations to reduce build-up of dental plaque and associated oral diseases.

Changes at the cell surface enable bacteria to survive in dynamic environments, such as diverse niches of the human host. Here, we reveal “Periscope Proteins” as a widespread mechanism of bacterial surface alteration mediated through protein length variation. Tandem arrays of highly similar folded domains can form an elongated rod-like structure; thus, variation in the number of domains determines how far an N-terminal host ligand binding domain projects from the cell surface. Supported by newly available long-read genome sequencing data, we propose that this class could contain over 50 distinct proteins, including those implicated in host colonization and biofilm formation by human pathogens. In large multidomain proteins, sequence divergence between adjacent domains appears to reduce interdomain misfolding. Periscope Proteins break this “rule,” suggesting that their length variability plays an important role in regulating bacterial interactions with host surfaces, other bacteria, and the immune system.

Recently, it has been reported that eriC and crcB are involved in bacterial fluoride resistance. However, the fluoride-resistance mechanism in oral streptococci remains unclear. BLAST studies showed that two types of eriCs (eriC1 and eriC2) and two types of crcBs (crcB1 and crcB2) are present across 18 oral streptococci, which were identified in ≥ 10% of 166 orally healthy subjects with ≥ 0.01% of the mean relative abundance. They were divided into three groups based on the distribution of these four genes: group I, only eriC1; group II, eriC1 and eriC2; and group III, eriC2, crcB1, and crcB2. Group I consisted of Streptococcus mutans, in which one of the two eriC1s predominantly affected fluoride resistance. Group II consisted of eight species, and eriC1 was responsible for fluoride resistance, but eriC2 was not, in Streptococcus anginosus as a representative species. Group III consisted of nine species, and both crcB1 and crcB2 were crucial for fluoride resistance, but eriC2 was not, in Streptococcus sanguinis as a representative species. Based on these results, either EriC1 or CrcBs play a role in fluoride resistance in oral streptococci. Complementation between S. mutans EriC1 and S. sanguinis CrcB1/CrcB2 was confirmed in both S. mutans and S. sanguinis. However, neither transfer of S. sanguinis CrcB1/CrcB2 into wild-type S. mutans nor S. mutans EriC1 into wild-type S. sanguinis increased the fluoride resistance of the wild-type strain. Co-existence of different F- channels (EriC and CrcB) did not cause the additive effect on fluoride resistance in oral Streptococcus species.