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Cell Feb 2024Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse...
Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse stomach and induced acute gastritis. S. anginosus infection spontaneously induced progressive chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional mice, and the findings were confirmed in germ-free mice. In addition, S. anginosus accelerated GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Consistently, S. anginosus disrupted gastric barrier function, promoted cell proliferation, and inhibited apoptosis. Mechanistically, we identified an S. anginosus surface protein, TMPC, that interacts with Annexin A2 (ANXA2) receptor on gastric epithelial cells. Interaction of TMPC with ANXA2 mediated attachment and colonization of S. anginosus and induced mitogen-activated protein kinase (MAPK) activation. ANXA2 knockout abrogated the induction of MAPK by S. anginosus. Thus, this study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis.
Topics: Animals; Humans; Mice; Atrophy; Carcinogenesis; Cell Transformation, Neoplastic; Gastric Mucosa; Gastritis; Inflammation; Mitogen-Activated Protein Kinases; Stomach Neoplasms; Streptococcus anginosus; Streptococcal Infections
PubMed: 38295787
DOI: 10.1016/j.cell.2024.01.004 -
Clinical Microbiology and Infection :... Mar 2024Patients with bacteraemia caused by gram-positive bacteria are at risk for infective endocarditis (IE). Because IE needs long antibiotic treatment and sometimes heart... (Review)
Review
BACKGROUND
Patients with bacteraemia caused by gram-positive bacteria are at risk for infective endocarditis (IE). Because IE needs long antibiotic treatment and sometimes heart valve surgery, it is very important to identify patients with IE.
OBJECTIVES
In this narrative review we present and discuss how to determine which investigations to detect IE that are needed in individual patients with gram-positive bacteraemia.
SOURCES
Published original studies and previous reviews in English, within the relevant field are used.
CONTENT
First, the different qualities of the bacteraemia in relation to IE risk are discussed. The risk for IE in bacteraemia is related to the species of the bacterium but also to monomicrobial bacteraemia and the number of positive cultures. Second, patient-related factors for IE risk in bacteraemia are presented. Next, the risk stratification systems to determine the risk for IE in gram-positive bacteraemia caused by Staphylococcus aureus, viridans streptococci, and Enterococcus faecalis are presented and their use is discussed. In the last part of the review, an account for the different modalities of IE-investigations is given. The main focus is on echocardiography, which is the cornerstone of IE-investigations. Furthermore, F-fluorodesoxyglucose positron emission tomography/computed tomography and cardiac computed tomography are presented and their use is also discussed. A brief account for investigations used to identify embolic phenomena in IE is also given. Finally, we present a flowchart suggesting which investigations to perform in relation to IE in patients with gram-positive bacteraemia.
IMPLICATIONS
For the individual patient as well as the healthcare system, it is important both to diagnose IE and to decide when to stop looking for IE. This review might be helpful in finding that balance.
Topics: Humans; Endocarditis; Endocarditis, Bacterial; Staphylococcal Infections; Staphylococcus aureus; Bacteremia
PubMed: 37659693
DOI: 10.1016/j.cmi.2023.08.027 -
Frontiers in Cellular and Infection... 2024Streptococci are primary colonizers of the oral cavity where they are ubiquitously present and an integral part of the commensal oral biofilm microflora. The role oral... (Review)
Review
Streptococci are primary colonizers of the oral cavity where they are ubiquitously present and an integral part of the commensal oral biofilm microflora. The role oral streptococci play in the interaction with the host is ambivalent. On the one hand, they function as gatekeepers of homeostasis and are a prerequisite for the maintenance of oral health - they shape the oral microbiota, modulate the immune system to enable bacterial survival, and antagonize pathogenic species. On the other hand, also recognized pathogens, such as oral and , which trigger the onset of dental caries belong to the genus . In the context of periodontitis, oral streptococci as excellent initial biofilm formers have an accessory function, enabling late biofilm colonizers to inhabit gingival pockets and cause disease. The pathogenic potential of oral streptococci fully unfolds when their dissemination into the bloodstream occurs; streptococcal infection can cause extra-oral diseases, such as infective endocarditis and hemorrhagic stroke. In this review, the taxonomic diversity of oral streptococci, their role and prevalence in the oral cavity and their contribution to oral health and disease will be discussed, focusing on the virulence factors these species employ for interactions at the host interface.
Topics: Humans; Dental Caries; Streptococcus; Streptococcus mutans; Streptococcus sobrinus; Mouth; Biofilms
PubMed: 38456080
DOI: 10.3389/fcimb.2024.1357631 -
Frontiers in Cellular and Infection... 2023
Topics: Dental Caries Susceptibility; Biofilms; Streptococcus mutans
PubMed: 38106468
DOI: 10.3389/fcimb.2023.1332907 -
Microbiology Spectrum Aug 2023Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) genes are widely recognized as bacterial adaptive immune systems against...
Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) genes are widely recognized as bacterial adaptive immune systems against invading viruses and bacteriophages. The oral pathogen Streptococcus mutans encodes two CRISPR-Cas loci (CRISPR1-Cas and CRISPR2-Cas), and their expression under environmental conditions is still under investigation. In this study, we investigated the transcriptional regulation of operons by CcpA and CodY, two global regulators that contribute to carbohydrate and (p)ppGpp metabolism. The possible promoter regions for operons and the binding sites for CcpA and CodY in the promoter regions of both CRISPR-Cas loci were predicted using computational algorithms. We found that CcpA could directly bind to the upstream region of both operons, and detected an allosteric interaction of CodY within the same region. The binding sequences of the two regulators were identified through footprinting analysis. Our results showed that the promoter activity of CRISPR1-Cas was enhanced under fructose-rich conditions, while deletion of the gene led to reduced activity of the CRISPR2-Cas promoter under the same conditions. Additionally, deletion of the CRISPR systems resulted in a significant decrease in fructose uptake ability compared to the parental strain. Interestingly, the accumulation of guanosine tetraphosphate (ppGpp) was reduced in the presence of mupirocin, which induces a stringent response, in the CRISPR1-Cas-deleted (ΔCR1) and both CRISPR-Cas-deleted (ΔCRD) mutant strains. Furthermore, the promoter activity of both CRISPRs was enhanced in response to oxidative or membrane stress, while the CRISPR1 promoter activity was reduced under low-pH conditions. Collectively, our findings demonstrate that the transcription of the CRISPR-Cas system is directly regulated by the binding of CcpA and CodY. These regulatory actions play a crucial role in modulating glycolytic processes and exerting effective CRISPR-mediated immunity in response to nutrient availability and environmental cues. An effective immune system has evolved not only in eukaryotic organisms but also in microorganisms, enabling them to rapidly detect and neutralize foreign invaders in the environment. Specifically, the CRISPR-Cas system in bacterial cells is established through a complex and sophisticated regulatory mechanism involving specific factors. In this study, we demonstrate that the expression of two CRISPR systems in S. mutans can be controlled by two global regulators, CcpA and CodY, which play critical roles in carbohydrate metabolism and amino acid biosynthesis. Importantly, our results show that the expression of the CRISPR-Cas system in S. mutans influences (p)ppGpp production during the stringent response, which is a gene expression regulatory response that aids in environmental stress adaptation. This transcriptional regulation by these regulators enables a CRISPR-mediated immune response in a host environment with limited availability of carbon sources or amino acids, while ensuring efficient carbon flux and energy expenditure to support multiple metabolic processes.
Topics: CRISPR-Cas Systems; Streptococcus mutans; Guanosine Pentaphosphate; Promoter Regions, Genetic; Fructose; Bacterial Proteins
PubMed: 37367300
DOI: 10.1128/spectrum.01826-23 -
Infection and Immunity Mar 2024Oral streptococci, key players in oral biofilm formation, are implicated in oral dysbiosis and various clinical conditions, including dental caries, gingivitis,...
Oral streptococci, key players in oral biofilm formation, are implicated in oral dysbiosis and various clinical conditions, including dental caries, gingivitis, periodontal disease, and oral cancer. Specifically, is associated with esophageal, gastric, and pharyngeal cancers, while is linked to oral cancer. However, no study has investigated the mechanistic links between these species and cancer-related inflammatory responses. As an initial step, we probed the innate immune response triggered by and in RAW264.7 macrophages. These bacteria exerted time- and dose-dependent effects on macrophage morphology without affecting cell viability. Compared with untreated macrophages, macrophages infected with exhibited a robust proinflammatory response characterized by significantly increased levels of inflammatory cytokines and mediators, including TNF, IL-6, IL-1β, NOS2, and COX2, accompanied by enhanced NF-κB activation. In contrast, -infected macrophages failed to elicit a robust inflammatory response. Seahorse Xfe96 analysis revealed an increased extracellular acidification rate in macrophages infected with compared with . At the 24-h time point, the presence of led to reduced extracellular itaconate, while triggered increased itaconate levels, highlighting distinct metabolic profiles in macrophages during infection in contrast to aconitate decarboxylase expression observed at the 6-h time point. This initial investigation highlights how and , two Gram-positive bacteria from the same genus, can prompt distinct immune responses and metabolic shifts in macrophages during infection.IMPORTANCEThe surge in head and neck cancer cases among individuals devoid of typical risk factors such as Human Papilloma Virus (HPV) infection and tobacco and alcohol use sparks an argumentative discussion around the emerging role of oral microbiota as a novel risk factor in oral squamous cell carcinoma (OSCC). While substantial research has dissected the gut microbiome's influence on physiology, the oral microbiome, notably oral streptococci, has been underappreciated during mucosal immunopathogenesis. , a viridans streptococci group, has been linked to abscess formation and an elevated presence in esophageal cancer and OSCC. The current study aims to probe the innate immune response to compared with the early colonizer as an important first step toward understanding the impact of distinct oral species on the host immune response, which is an understudied determinant of OSCC development and progression.
Topics: Humans; Streptococcus anginosus; Carcinoma, Squamous Cell; Mouth Neoplasms; Dental Caries; Streptococcus; Macrophages; Succinates
PubMed: 38289109
DOI: 10.1128/iai.00536-23 -
The ISME Journal Jul 2023During oral biofilm development, interspecies interactions drive species distribution and biofilm architecture. To understand what molecular mechanisms determine these...
During oral biofilm development, interspecies interactions drive species distribution and biofilm architecture. To understand what molecular mechanisms determine these interactions, we used information gained from recent biogeographical investigations demonstrating an association of corynebacteria with streptococci. We previously reported that Streptococcus sanguinis and Corynebacterium durum have a close relationship through the production of membrane vesicle and fatty acids leading to S. sanguinis chain elongation and overall increased fitness supporting their commensal state. Here we present the molecular mechanisms of this interspecies interaction. Coculture experiments for transcriptomic analysis identified several differentially expressed genes in S. sanguinis. Due to its connection to fatty acid synthesis, we focused on the glycerol-operon. We further explored the differentially expressed type IV pili genes due to their connection to motility and biofilm adhesion. Gene inactivation of the glycerol kinase glpK had a profound impact on the ability of S. sanguinis to metabolize C. durum secreted glycerol and impaired chain elongation important for their interaction. Investigations on the effect of type IV pili revealed a reduction of S. sanguinis twitching motility in the presence of C. durum, which was caused by a decrease in type IV pili abundance on the surface of S. sanguinis as determined by SEM. In conclusion, we identified that the ability to metabolize C. durum produced glycerol is crucial for the interaction of C. durum and S. sanguinis. Reduced twitching motility could lead to a closer interaction of both species, supporting niche development in the oral cavity and potentially shaping symbiotic health-associated biofilm communities.
Topics: Glycerol; Streptococcus; Streptococcus sanguis; Biofilms; Symbiosis; Streptococcus mutans
PubMed: 37169870
DOI: 10.1038/s41396-023-01426-9 -
Virulence Dec 2023is a ubiquitous commensal species of the oral cavity commonly involved as an opportunistic pathogen in cardiovascular infections. In this study, we investigated the...
is a ubiquitous commensal species of the oral cavity commonly involved as an opportunistic pathogen in cardiovascular infections. In this study, we investigated the functions of endopeptidase O (PepO) and a C3-degrading protease (CppA) in the systemic virulence of . Isogenic mutants of and obtained in strain SK36 showed increased susceptibility to C3b deposition and to opsonophagocytosis by human polymorphonuclear neutrophils (PMN). These mutants differ, however, in their profiles of binding to serum amyloid P component (SAP) and C1q, whereas both showed reduced interaction with C4b-binding protein (C4BP) and/or factor H (FH) regulators as compared to SK36. The two mutants showed defects in persistence in human blood, serum-mediated invasion of HCAEC endothelial cells, and virulence in a infection model. The transcriptional activities of and , assessed by RT-qPCR in nine wild-type strains, further indicated strain-specific profiles of / expression. Moreover, non-conserved amino acid substitutions were detected among the strains, mostly in CppA. Phylogenetic comparisons with homologues of streptococcal species of the oral and oropharyngeal sites suggested that PepO and CppA have independent ancestralities. Thus, this study showed that PepO and CppA are complement evasion proteins expressed by in a strain-specific manner, which are required for multiple functions associated with cardiovascular virulence.
Topics: Humans; Streptococcus sanguis; Virulence; Endothelial Cells; Phylogeny; Complement System Proteins; Bacterial Proteins
PubMed: 37563831
DOI: 10.1080/21505594.2023.2239519 -
BMC Oral Health Sep 2023The review aims to determine the risk predictability of mutans streptococci in the development of carious lesions in children with primary dentition. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The review aims to determine the risk predictability of mutans streptococci in the development of carious lesions in children with primary dentition.
METHODS
Longitudinal observational studies with at least 6 months follow-up and evaluating mutans streptococci presence in caries-free children under 6 years of age for the development of any cavitated or non-cavitated carious lesion. Six databases and grey literature were searched without any restrictions. Risk of bias was evaluated using the New Castle Ottawa scale for longitudinal studies, and the certainty of the evidence was evaluated by Grading of Recommendations Assessment, Development and Evaluation using GRADEpro software. Meta-analysis was performed using a random effect (DerSimonian and Laird, DL) model, and heterogeneity was evaluated using tau-squared, I statistics and prediction interval. Sensitivity analysis was performed to assess the relationship between the mutans streptococci presence at baseline and the caries development, according to the sample and methods used for the microbiological assessment and the length of follow-up of the studies. Publication bias was checked by funnel plot using a random effect (DerSimonian and Laird, DL) model.
RESULTS
Twelve studies met the inclusion criteria and were included in the review. Four studies received a maximum of 9 stars, and among the remaining eight studies, six received 8 stars and the rest two studies were assigned 7 stars in the risk of bias scale. After pooling the results quantitatively, odds ratio (OR) was found to be 4.13 (95% CI: 3.33, 5.12), suggesting that children with mutans streptococci had 4 times higher odds of developing caries later (p < 0.001). Four studies were pooled to compare future caries experience among children with and without mutans streptococci at baseline, obtaining standardized mean difference (SMD) of 0.85 (95% CI: 0.33, 1.37), indicating a large effect (p < 0.001). Certainty of evidence was found to be moderate, and no publication bias was reported by the funnel plot criteria of symmetry.
CONCLUSIONS
Presence of mutans streptococci in a preschool child is a risk predictor for future caries experience. Early identification of children with increased caries-risk may facilitate in implementation of appropriate preventive strategies.
Topics: Humans; Child, Preschool; Dental Caries; Databases, Factual; Odds Ratio; Publication Bias; Software; Streptococcus mutans
PubMed: 37679718
DOI: 10.1186/s12903-023-03346-8 -
International Journal of Nanomedicine 2023Effective infection control without irritating the pulp tissue is the key to successful vital pulp therapy. Developing a novel antibacterial biomaterial that promotes...
INTRODUCTION
Effective infection control without irritating the pulp tissue is the key to successful vital pulp therapy. Developing a novel antibacterial biomaterial that promotes dentin regeneration for pulp capping is thus a promising strategy for enhancing vital pulp therapy.
METHODS
Lithium-doped mesoporous nanoparticles (Li-MNPs) were synthesized using an alkali-catalyzed sol-gel method. The particle size, elemental distribution, surface morphology, pore structure, and ion release from Li-MNPs were measured. Human dental pulp stem cells (hDPSCs) and () were used to evaluate the biological effects of Li-MNPs. In addition, a dental pulp exposure mouse model was used to evaluate the regenerative effects of Li-MNPs.
RESULTS
Li-MNPs had a larger surface area (221.18 m/g), a larger pore volume (0.25 cm/g), and a smaller particle size (520.92 ± 35.21 nm) than MNPs. The in vitro investigation demonstrated that Li-MNPs greatly enhanced the biomineralization and odontogenic differentiation of hDPSCs through the Wnt/β-catenin signaling pathway. Li-MNPs showed a strong antibacterial effect on . As expected, Li-MNPs significantly promoted dentin regeneration in situ and in vivo.
CONCLUSION
Li-MNPs promoted dentin regeneration and inhibited growth, implying a possible application as a pulp capping agent in vital pulp therapy.
Topics: Humans; Animals; Mice; Lithium; Nanoparticles; Anti-Bacterial Agents; Streptococcus mutans; Regeneration; Dentin
PubMed: 37746049
DOI: 10.2147/IJN.S424930