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ObjectiveAlteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis.MethodsWe performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals (N case=47, N control=203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data.ResultsVia species level phylogenetic analysis, we identified and validated increases of Streptococcus intermedius and Streptococcus anginosus in the patients with SLE. Microbial gene analysis revealed increases of Streptococcus-derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). α-diversity and β-diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with Streptococcus intermedius, an SLE-associated taxon.ConclusionOur MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE.

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.

SMG species are increasingly being recognized as pathogens. Despite their clinical relevance, little is known about how SMG members transition between asymptomatic colonization and infection. Herein, we show that clinical isolates of S. intermedius can be classified into four groups based on their aggregation and adherent biofilm phenotypes. We demonstrate that aggregation is dependent on the Pel polysaccharide and that Pel production allows bacteria not only to persist longer during infection but also modulates the immune responses of the host. Pel production requires the canonical pelDEA DA FG genes. We also identified four additional genes in the S. intermedius pel cluster and found that under the conditions tested, two of these genes play a role in aggregation and Pel production. Functional homologs of the additional genes play major roles in host-pathogen interactions and stress responses in other bacteria, suggesting that these additional genes could play a role in Pel-related infections.

Abstract Streptococcus intermedius secretes the human-specific cytolysin intermedilysin (ILY), a crucial factor in the pathogenicity of this bacterium. Previously, we reported that a lactose phosphotransferase repressor (LacR) represses ily expression, and that its mutation increases ILY production. Interestingly, UNS40, a strain isolated from a liver abscess, produces high levels of ILY despite the absence of mutations in the lacR promoter and coding regions. Our results showed that a G > A mutation at the −90th position from the transcription start point in the UNS40 ily promoter region increased hemolytic activity and decreased the binding ability to LacR. To elucidate the regions involved in the repression of ily expression, we generated mutant strains, in which point or deletion mutations were introduced into the ily promoter region, and then compared their hemolytic activity. Among the point mutations, −120 C > A and −90 G > A and their flanking mutations increased hemolytic activity. These results indicated that these mutations may increase the virulence of S. intermedius. Identified point mutations in the ILY promoter responsible for upregulated ily gene expression.

Infectious diseases of the central nervous system are commonly characterized by delayed diagnosis due to the diversity of pathogens, subtle clinical symptoms, and nonspecific early imaging findings. These diseases are associated with high morbidity and mortality rates. This report presents a rare case of intracranial mixed infection caused by co-infection with Streptococcus intermedius and torque teno virus. This report involves a retrospective analysis of the clinical features, laboratory investigations, and treatment outcomes of intracranial infection, along with diagnostic and therapeutic strategies for such rare mixed infections. The results demonstrated that cerebrospinal fluid metagenomic sequencing plays a crucial role in the microbiological diagnosis of intracranial mixed infection. This report describes the case of a man in his late 30s in whom Streptococcus intermedius and torque teno virus were simultaneously detected in the cerebrospinal fluid. The infection exhibited rapid progression and high aggressiveness, significantly increasing the risk of mortality. This study emphasizes the invasive clinical course of this infection. Despite active and intensive treatment, the patient ultimately succumbed to the illness. It remains unclear whether torque teno virus infection plays a direct role in the pathogenesis or contributes to the severity of the intracranial mixed infection. This case highlights the importance of multidisciplinary collaboration in the diagnosis and treatment of complex intracranial infections, providing clinicians with a novel approach for the differential diagnosis of mixed infections and increasing the clinical awareness and understanding of such rare mixed infections involving the central nervous system.

The terminology and classification of the Anginosus group streptococci has been inconsistent. We tested the utility of 16S rRNA gene and tuf gene sequencing and conventional biochemical tests for the reliable differentiation of the Anginosus group streptococci. Biochemical testing included Rapid ID 32 Strep, API Strep, Fluo-Card Milleri, Wee-tabs, and Lancefield antigen typing. Altogether, 61 Anginosus group isolates from skin and soft tissue infections and four reference strains were included. Our results showed a good agreement between 16S rRNA gene and tuf gene sequencing. Using the full sequence was less discriminatory than using the first part of the 16S rRNA gene. The three species could not be separated with the API 20 Strep test. Streptococcus intermedius could be differentiated from the other two species by β-galactosidase (ONPG) and β-N-acetyl-glucosaminidase reactions. Rapid ID 32 Strep β-glucosidase reaction was useful in separating S. anginosus strains from S. constellatus. In conclusion, both 16S rRNA gene and tuf gene sequencing can be used for the reliable identification of the Anginosus group streptococci. S. intermedius can be readily differentiated from the other two species by phenotypic tests; however, 16S rRNA gene or tuf gene sequencing may be needed for separating some strains of S. constellatus from S. anginosus.

The aim of this study was to establish an identification method for the anginosus group within the genus Streptococcus by polymerase chain reaction (PCR). Using a primer pair based on the group-specific sequences of penicillin-binding protein 2B ( pbp2b) gene, a 275-bp fragment was amplified from each species in the group but no size-matched products were obtained in other streptococci. Further identification in the species or subspecies level was possible by a multiplex PCR with primers for the 16S ribosomal RNA gene of Streptococcus anginosus, the hyaluronate lyase genes both of Streptococcus intermedius and Streptococcus constellatus subsp. constellatus, and the intermedilysin ( ily) gene of S. intermedius. In the case of Streptococcus constellatus subsp. pharyngis, the amplified fragment from the S. intermedius-type hyaluronate lyase gene was obtained, while that from the ily gene was not. These results also indicate that two different hyaluronate lyase genes are distributed among the anginosus group.

A selected group of oral bacteria commonly associated with dental health is capable of producing alkali via the arginine deiminase system (ADS), which has a profound impact on the pH of human oral biofilms. An increased risk for dental caries has been associated with reduced ADS activity of the bacteria in oral biofilms. Arginolytic bacterial strains from dental plaque samples of caries-free and caries-active adults were isolated and characterized to investigate the basis for differences in plaque ADS activity between individuals. Fifty-six ADS-positive bacterial strains were identified by 16S rRNA gene sequencing, and their ADS activity levels were compared under standard growth conditions. The spectrum of bacterial ADS activity ranged from 45.2 to 688.0 units (mg protein) -1 . Although Streptococcus sanguinis was the most prevalent species, other Streptococcus sp. were also represented. Biochemical assays carried out using 27 ADS-positive strains under conditions known to induce or repress ADS gene expression showed substantial variation in arginolytic activity in response to pH, oxygen and the availability of carbohydrate or arginine. This study reveals that the basis for the wide spectrum of arginolytic expression observed among clinical strains is, at least in part, attributable to differences in the regulation of the ADS within and between species. The results provide insights into the microbiological basis for intersubject differences in ADS activity in oral biofilms and enhance our understanding of dental caries as an ecologically driven disease in which arginine metabolism moderates plaque pH and promotes dental health.

Background The Streptococcus Anginosus Group (SAG) represents three closely related species of the viridans group streptococci recognized as commensal bacteria of the oral, gastrointestinal and urogenital tracts. The SAG also cause severe invasive infections, and are pathogens during cystic fibrosis (CF) pulmonary exacerbation. Little genomic information or description of virulence mechanisms is currently available for SAG. We conducted intra and inter species whole-genome comparative analyses with 59 publically available Streptococcus genomes and seven in-house closed high quality finished SAG genomes; S. constellatus (3), S. intermedius (2), and S. anginosus (2). For each SAG species, we sequenced at least one numerically dominant strain from CF airways recovered during acute exacerbation and an invasive, non-lung isolate. We also evaluated microevolution that occurred within two isolates that were cultured from one individual one year apart. Results The SAG genomes were most closely related to S. gordonii and S. sanguinis , based on shared orthologs and harbor a similar number of proteins within each COG category as other Streptococcus species. Numerous characterized streptococcus virulence factor homologs were identified within the SAG genomes including; adherence, invasion, spreading factors, LPxTG cell wall proteins, and two component histidine kinases known to be involved in virulence gene regulation. Mobile elements, primarily integrative conjugative elements and bacteriophage, account for greater than 10% of the SAG genomes. S. anginosus was the most variable species sequenced in this study, yielding both the smallest and the largest SAG genomes containing multiple genomic rearrangements, insertions and deletions. In contrast, within the S. constellatus and S. intermedius species, there was extensive continuous synteny, with only slight differences in genome size between strains. Within S. constellatus we were able to determine important SNPs and changes in VNTR numbers that occurred over the course of one year. Conclusions The comparative genomic analysis of the SAG clarifies the phylogenetics of these bacteria and supports the distinct species classification. Numerous potential virulence determinants were identified and provide a foundation for further studies into SAG pathogenesis. Furthermore, the data may be used to enable the development of rapid diagnostic assays and therapeutics for these pathogens.

Background Periodontitis is a polymicrobial biofilm-induced inflammatory disease that affects 743 million people worldwide. The current model to explain periodontitis progression proposes that changes in the relative abundance of members of the oral microbiome lead to dysbiosis in the host-microbiome crosstalk and then to inflammation and bone loss. Using combined metagenome/metatranscriptome analysis of the subgingival microbiome in progressing and non-progressing sites, we have characterized the distinct molecular signatures of periodontitis progression. Methods Metatranscriptome analysis was conducted on samples from subgingival biofilms from progressing and stable sites from periodontitis patients. Community-wide expression profiles were obtained using Next Generation Sequencing (Illumina). Sequences were aligned using ‘bowtie2’ against a constructed oral microbiome database. Differential expression analysis was performed using the non-parametric algorithm implemented on the R package ‘NOISeqBio’. We summarized global functional activities of the oral microbial community by set enrichment analysis based on the Gene Ontology (GO) orthology. Results Gene ontology enrichment analysis showed an over-representation in the baseline of active sites of terms related to cell motility, lipid A and peptidoglycan biosynthesis, and transport of iron, potassium, and amino acids. Periodontal pathogens ( Tannerella forsythia and Porphyromonas gingivalis ) upregulated different TonB-dependent receptors, peptidases, proteases, aerotolerance genes, iron transport genes, hemolysins, and CRISPR-associated genes. Surprisingly, organisms that have not been usually associated with the disease ( Streptococcus oralis , Streptococcus mutans , Streptococcus intermedius , Streptococcus mitis , Veillonella parvula, and Pseudomonas fluorenscens ) were highly active transcribing putative virulence factors. We detected patterns of activities associated with progression of clinical traits. Among those we found that the profiles of expression of cobalamin biosynthesis, proteolysis, and potassium transport were associated with the evolution towards disease. Conclusions We identified metabolic changes in the microbial community associated with the initial stages of dysbiosis. Regardless of the overall composition of the community, certain metabolic signatures are consistent with disease progression. Our results suggest that the whole community, and not just a handful of oral pathogens, is responsible for an increase in virulence that leads to progression. Trial registration NCT01489839 , 6 December 2011.