RESUMO
Streptococcus gallolyticus subspecies pasteurianus is a subtype of Streptococcus bovis (S. bovis) that has become increasingly recognized as a sepsis-causing pathogen in neonates. It is well documented that S. bovis species have a predilection to both cardiac and gastrointestinal tissue, and in adult populations, isolating these organisms in the bloodstream often triggers further evaluation for co-morbid complications such as colon cancer or endocarditis. However, no such guidance currently exists in neonatal literature. We present a case of a preterm infant with S. gallolyticus subsp. pasteurianus bacteremia presenting as necrotizing enterocolitis (NEC) not previously described in the literature. Furthermore, through a complete diagnostic evaluation, including an echocardiogram, our patient was found to have the rare complication of endocarditis.
Assuntos
Enterocolite Necrosante , Recém-Nascido Prematuro , Infecções Estreptocócicas , Humanos , Recém-Nascido , Antibacterianos/uso terapêutico , Arterite/microbiologia , Bacteriemia/microbiologia , Enterocolite Necrosante/microbiologia , Doenças do Prematuro/microbiologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/microbiologia , Streptococcus gallolyticus subspecies gallolyticusRESUMO
BACKGROUND: Streptococcus gallolyticus subspecies pasteurianus (SGP), a subtype of Streptococcus bovis , is an uncommon but important cause of neonatal sepsis. Although uncommon, SGP infections during infancy have been associated with an increased risk of morbidity and mortality. METHODS: This is a systematic review and meta-analysis of available literature on the clinical course and outcomes of infants with SGP infection. Studies were identified using the following MeSH keywords: " Streptococcus gallolyticus ," " Streptococcus bovis ," "newborn" and "infant." Data including perinatal factors, clinical presentation, investigations, treatment and outcomes were extracted and analyzed. RESULTS: A total of 46 articles were identified (116 cases: 60 S. bovis , 56 SGP). The cases were predominantly term (52%), male (57%) and born via vaginal delivery (67%). The most common symptom was fever [67% (95% confidence interval (CI): 43%-84%)], lethargy [66% (95% CI: 32%-89%)], tachypnea [59% (95% CI: 27%-85%)] and irritability [59% (95% CI: 34%-79%)]. Infants with early-onset infections (<3 days of life) were more likely to have respiratory symptoms and bacteremia (73%), whereas late-onset infections presented predominantly with gastrointestinal symptoms. Four mortalities were reported which occurred before antibiotic administration. Isolated bacteria were mostly penicillin-susceptible [95% (95% CI: 78-99%)] and cases treated with penicillin derivative had good recovery. CONCLUSIONS: SGP is an important cause of neonatal sepsis and meningitis. Penicillin derivative is an effective treatment for SGP, and outcomes appear to be favorable.
Assuntos
Antibacterianos , Infecções Estreptocócicas , Streptococcus bovis , Humanos , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/mortalidade , Recém-Nascido , Lactente , Antibacterianos/uso terapêutico , Feminino , Streptococcus gallolyticus subspecies gallolyticus , Masculino , Resultado do Tratamento , Sepse Neonatal/microbiologia , Sepse Neonatal/tratamento farmacológico , Sepse Neonatal/mortalidadeRESUMO
Streptococcus gallolyticus sp. gallolyticus (SGG) is a gut pathobiont involved in the development of colorectal cancer (CRC). To decipher SGG contribution in tumor initiation and/or acceleration respectively, a global transcriptome was performed in human normal colonic cells (FHC) and in human tumoral colonic cells (HT29). To identify SGG-specific alterations, we chose the phylogenetically closest relative, Streptococcus gallolyticus subsp. macedonicus (SGM) as control bacterium. We show that SGM, a bacterium generally considered as safe, did not induce any transcriptional changes on the two human colonic cells. The transcriptional reprogramming induced by SGG in normal FHC and tumoral HT29 cells was significantly different, although most of the genes up- and down-regulated were associated with cancer disease. Top up-regulated genes related to cancer were: (i) IL-20, CLK1, SORBS2, ERG1, PIM1, SNORD3A for normal FHC cells and (ii) TSLP, BHLHA15, LAMP3, ZNF27B, KRT17, ATF3 for cancerous HT29 cells. The total number of altered genes were much higher in cancerous than in normal colonic cells (2,090 vs 128 genes being affected, respectively). Gene set enrichment analysis reveals that SGG-induced strong ER- (endoplasmic reticulum) stress and UPR- (unfolded protein response) activation in colonic epithelial cells. Our results suggest that SGG induces a pro-tumoral shift in human colonic cells particularly in transformed cells potentially accelerating tumor development in the colon.
Assuntos
Neoplasias Colorretais , Infecções Estreptocócicas , Streptococcus gallolyticus subspecies gallolyticus , Humanos , Neoplasias Colorretais/microbiologia , Streptococcus , Perfilação da Expressão Gênica , Infecções Estreptocócicas/microbiologia , Streptococcus gallolyticus/genéticaRESUMO
In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of several cancer hallmark pathways such as MAPK, mTOR and integrin/ILK/actin, affecting epithelial and stromal colonic cells. Importantly, an independent analysis of protein arrays of human colon tumors colonized with SGG showed up-regulation of PI3K/Akt/mTOR and MAPK pathways, providing clinical relevance to our findings. To test SGG's capacity to induce pre-cancerous transformation of the murine colonic epithelium, we grew ex vivo organoids which revealed unusual structures with compact morphology. Taken together, our results demonstrate the oncogenic role of SGG UCN34 in a murine model of CRC associated with activation of multiple cancer-related signaling pathways.
Assuntos
Neoplasias do Colo , Streptococcus gallolyticus subspecies gallolyticus , Humanos , Animais , Camundongos , Modelos Animais de Doenças , Fosfatidilinositol 3-Quinases , Proteômica , Serina-Treonina Quinases TOR , Fosfoproteínas , Proteoma , Transdução de SinaisRESUMO
Streptococcus gallolyticus subsp. gallolyticus (SGG) is an opportunistic bacterial pathogen strongly associated with colorectal cancer. Here, through comparative genomics analysis, we demonstrated that the genetic locus encoding the type VIIb secretion system (T7SSb) machinery is uniquely present in SGG in two different arrangements. SGG UCN34 carrying the most prevalent T7SSb genetic arrangement was chosen as the reference strain. To identify the effectors secreted by this secretion system, we inactivated the essC gene encoding the motor of this machinery. A comparison of the proteins secreted by UCN34 wild type and its isogenic ΔessC mutant revealed six T7SSb effector proteins, including the expected WXG effector EsxA and three LXG-containing proteins. In this work, we characterized an LXG-family toxin named herein TelE promoting the loss of membrane integrity. Seven homologs of TelE harboring a conserved glycine zipper motif at the C terminus were identified in different SGG isolates. Scanning mutagenesis of this motif showed that the glycine residue at position 470 was crucial for TelE membrane destabilization activity. TelE activity was antagonized by a small protein TipE belonging to the DUF5085 family. Overall, we report herein a unique SGG T7SSb effector exhibiting a toxic activity against nonimmune bacteria. IMPORTANCE In this study, 38 clinical isolates of Streptococcus gallolyticus subsp. gallolyticus (SGG) were sequenced and a genetic locus encoding the type VIIb secretion system (T7SSb) was found conserved and absent from 16 genomes of the closely related S. gallolyticus subsp. pasteurianus (SGP). The T7SSb is a bona fide pathogenicity island. Here, we report that the model organism SGG strain UCN34 secretes six T7SSb effectors. One of the six effectors named TelE displayed a strong toxicity when overexpressed in Escherichia coli. Our results indicate that TelE is probably a pore-forming toxin whose activity can be antagonized by a specific immunity protein named TipE. Overall, we report a unique toxin-immunity protein pair and our data expand the range of effectors secreted through T7SSb.
Assuntos
Motivos de Aminoácidos , Streptococcus gallolyticus subspecies gallolyticus , Sistemas de Secreção Tipo VII , Streptococcus gallolyticus subspecies gallolyticus/genética , GlicinaRESUMO
Streptococcus gallolyticus subspecies gallolyticus (Sgg) is known to be strongly associated with colorectal cancer (CRC). Recent functional studies further demonstrated that Sgg actively stimulates CRC cell proliferation and promotes the development of colon tumors. However, the Sgg factors important for the pro-proliferative and pro-tumor activities of Sgg remain unclear. Here, we identified a chromosomal locus in Sgg strain TX20005. Deletion of this locus significantly reduced Sgg adherence to CRC cells and abrogated the ability of Sgg to stimulate CRC cell proliferation. Thus, we designate this locus as the Sgg pathogenicity-associated region (SPAR). More importantly, we found that SPAR is important for Sgg pathogenicity in vivo. In a gut colonization model, mice exposed to the SPAR deletion mutant showed significantly reduced Sgg load in the colonic tissues and fecal materials, suggesting that SPAR contributes to the colonization capacity of Sgg. In a mouse model of CRC, deletion of SPAR abolished the ability of Sgg to promote the development of colon tumors growth. Taken together, these results highlight SPAR as a critical pathogenicity determinant of Sgg.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Infecções Estreptocócicas , Streptococcus gallolyticus subspecies gallolyticus , Animais , Camundongos , Streptococcus gallolyticus subspecies gallolyticus/genética , Virulência/genética , Neoplasias Colorretais/patologia , Neoplasias do Colo/complicações , Infecções Estreptocócicas/complicaçõesRESUMO
Streptococcus gallolyticus subspecies gallolyticus (Sgg) has a strong clinical association with colorectal cancer (CRC) and actively promotes the development of colon tumors. Previous work showed that this organism stimulates CRC cells proliferation and tumor growth. However, the molecular mechanisms underlying these activities are not well understood. Here, we found that Sgg upregulates the expression of several type of collagens in HT29 and HCT116 cells, with type VI collagen (ColVI) being the highest upregulated type. Knockdown of ColVI abolished the ability of Sgg to induce cell proliferation and reduced the adherence of Sgg to CRC cells. The extracellular matrix (ECM) is an important regulator of cell proliferation. Therefore, we further examined the role of decellularized matrix (dc-matrix), which is free of live bacteria or cells, in Sgg-induced cell proliferation. Dc-matrix prepared from Sgg-treated cells showed a significantly higher pro-proliferative activity than that from untreated cells or cells treated with control bacteria. On the other hand, dc-matrix from Sgg-treated ColVI knockdown cells showed no difference in the capacity to support cell proliferation compared to that from untreated ColVI knockdown cells, suggesting that the ECM by itself is a mediator of Sgg-induced cell proliferation. Furthermore, Sgg treatment of CRC cells but not ColVI knockdown CRC cells resulted in significantly larger tumors in vivo, suggesting that ColVI is important for Sgg to promote tumor growth in vivo. These results highlight a dynamic bidirectional interplay between Sgg and the ECM, where Sgg upregulates collagen expression. The Sgg-modified ECM in turn affects the ability of Sgg to adhere to host cells and more importantly, acts as a mediator for Sgg-induced CRC cell proliferation. Taken together, our results reveal a novel mechanism in which Sgg stimulates CRC proliferation through modulation of the ECM.
Assuntos
Neoplasias Colorretais , Streptococcus gallolyticus subspecies gallolyticus , Proliferação de Células , Colágeno Tipo VI , Neoplasias Colorretais/microbiologia , Matriz Extracelular/patologia , Humanos , Streptococcus gallolyticus subspecies gallolyticus/fisiologiaRESUMO
Streptococcus gallolyticus subspecies gallolyticus (Sgg) has a strong clinical association with colorectal cancer (CRC) and actively promotes the development of colon tumors. However, the molecular determinants involved in Sgg pathogenicity in the gut are unknown. Bacterial type VII secretion systems (T7SS) mediate pathogen interactions with their host and are important for virulence in pathogenic mycobacteria and Staphylococcus aureus. Through genome analysis, we identified a locus in Sgg strain TX20005 that encodes a putative type VII secretion system (designated as SggT7SST05). We showed that core genes within the SggT7SST05 locus are expressed in vitro and in the colon of mice. Western blot analysis showed that SggEsxA, a protein predicted to be a T7SS secretion substrate, is detected in the bacterial culture supernatant, indicating that this SggT7SST05 is functional. Deletion of SggT7SST05 (TX20005Δesx) resulted in impaired bacterial adherence to HT29 cells and abolished the ability of Sgg to stimulate HT29 cell proliferation. Analysis of bacterial culture supernatants suggest that SggT7SST05-secreted factors are responsible for the pro-proliferative activity of Sgg, whereas Sgg adherence to host cells requires both SggT7SST05-secreted and bacterial surface-associated factors. In a murine gut colonization model, TX20005Δesx showed significantly reduced colonization compared to the parent strain. Furthermore, in a mouse model of CRC, mice exposed to TX20005 had a significantly higher tumor burden compared to saline-treated mice, whereas those exposed to TX20005Δesx did not. Examination of the Sgg load in the colon in the CRC model suggests that SggT7SST05-mediated activities are directly involved in the promotion of colon tumors. Taken together, these results reveal SggT7SST05 as a previously unrecognized pathogenicity determinant for Sgg colonization of the colon and promotion of colon tumors.
Assuntos
Proliferação de Células , Neoplasias do Colo/patologia , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus gallolyticus subspecies gallolyticus/fisiologia , Sistemas de Secreção Tipo VII/metabolismo , Animais , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos A , Infecções Estreptocócicas/metabolismoRESUMO
The tannase-producing Gram-positive bacterial species Streptococcus gallolyticus subsp. gallolyticus (Sgg) is an opportunistic pathogen of the human gut and strongly associated with colorectal cancer (CRC). A unique feature of Sgg is its ability to degrade tannic acids (TA). TA constitute an important part of the human diet with known anti-tumorigenic properties. Here, we examined whether Sgg is able to protect tumor cells from the toxic effect of TA and thus drive tumorigenesis indirectly. Human CRC cell lines (n = 8) were treated with increasing concentrations of TA. We confirmed the cytotoxic activity of TA in a dose-dependent manner. In virtually all cell lines, viability decreased significantly (>60% inhibition). Moreover, pyrogallol, the degradation product of TA, had no effect on the tested cell lines. This suggests a specific effect of TA. Cytotoxicity was due to necrosis and induction of senescence in residual cells. Finally, when TA was degraded by Sgg, the cytotoxic effect could be abolished. Tumor cells even responded with boosted cell proliferation, highlighting the impact of Sgg on CRC progression. We here provide another piece of evidence for the active interplay between Sgg and cancer preventive components. These data will help to move forward in designing concepts for therapeutic and eventually also prophylactic approaches to combat gastrointestinal malignancies.
Assuntos
Biotransformação , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/patologia , Streptococcus gallolyticus subspecies gallolyticus/fisiologia , Taninos/metabolismo , Taninos/farmacologia , Antineoplásicos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Invasividade Neoplásica , Fitoterapia , Streptococcus gallolyticus , Taninos/uso terapêuticoRESUMO
The increasing threat of Streptococcus gallolyticus subsp. gallolyticus (SGG) infections has gained considerable attention for its strong association with colorectal cancer (CRC). Herein, we proposed real-time fluorescence loop-mediated isothermal amplification (LAMP) as a novel, simple, rapid, and highly sensitive assay for identifying SGG for the first time. This assay was capable of detecting SGG with initial DNA concentrations ranging from 102 to 108 copies per microliter, under isothermal conditions within 30 min via real-time fluorescence monitoring. Our method was tested for specific identification of SGG strains without cross-reaction with other Streptococcus gallolyticus subspecies and Escherichia coli. The developed LAMP shows a superior performance with shorter time and higher sensitivity compared with conventional polymerase chain reaction (PCR). Significantly, this proposed approach was successfully applied for detecting SGG in clinical urine samples, which is non-invasive diagnosis, showing excellent accuracy and reliability to discriminate healthy controls and CRC patients. For comparison, these samples were also tested against PCR assay. These results yielded an analytical sensitivity of 100% and a specificity of 100% for SGG testing using LAMP. The findings suggest LAMP can be employed for detecting SGG infections which is useful for diagnosis and screening of CRC.
Assuntos
Neoplasias Colorretais/microbiologia , DNA Bacteriano/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Streptococcus gallolyticus subspecies gallolyticus/genética , Adulto , Idoso , Neoplasias Colorretais/urina , DNA Bacteriano/isolamento & purificação , Feminino , Fluorescência , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Amplificação de Ácido Nucleico/economia , Streptococcus gallolyticus subspecies gallolyticus/isolamento & purificação , Fatores de TempoRESUMO
Cyclic di-AMP is a recently identified second messenger exploited by a number of Gram-positive bacteria to regulate important biological processes. Here, we studied the phenotypic alterations induced by the increased intracellular c-di-AMP levels in Streptococcus gallolyticus, an opportunistic pathogen responsible for septicemia and endocarditis in the elderly. We report that an S. gallolyticus c-di-AMP phosphodiesterase gdpP knockout mutant, which displays a 1.5-fold higher intracellular c-di-AMP levels than the parental strain UCN34, is more sensitive to osmotic stress and is morphologically smaller than the parental strain. Unexpectedly, we found that a higher level of c-di-AMP reduced biofilm formation of S. gallolyticus on abiotic surfaces and reduced adherence and cell aggregation on human intestinal cells. A genome-wide transcriptomic analysis indicated that c-di-AMP regulates many biological processes in S. gallolyticus, including the expression of various ABC transporters and disease-associated genes encoding bacteriocin and Pil3 pilus. Complementation of the gdpP in-frame deletion mutant with a plasmid carrying gdpP in trans from its native promoter restored bacterial morphology, tolerance to osmotic stress, biofilm formation, adherence to intestinal cells, bacteriocin production, and Pil3 pilus expression. Our results indicate that c-di-AMP is a pleiotropic signaling molecule in S. gallolyticus that may be important for S. gallolyticus pathogenesis.IMPORTANCEStreptococcus gallolyticus is an opportunistic pathogen responsible for septicemia and endocarditis in the elderly and is also strongly associated with colorectal cancer. S. gallolyticus can form biofilms, express specific pili to colonize the host tissues, and produce a specific bacteriocin allowing killing of commensal bacteria in the murine colon. Nevertheless, how the expression of these colonization factors is regulated remains largely unknown. Here, we show that c-di-AMP plays pleiotropic roles in S. gallolyticus, controlling the tolerance to osmotic stress, cell size, biofilm formation on abiotic surfaces, adherence and cell aggregation on human intestinal cells, expression of Pil3 pilus, and production of bacteriocin. This study indicates that c-di-AMP may constitute a key regulatory molecule for S. gallolyticus host colonization and pathogenesis.
Assuntos
Aderência Bacteriana , Biofilmes/crescimento & desenvolvimento , Citosol/química , Fosfatos de Dinucleosídeos/análise , Pressão Osmótica , Streptococcus gallolyticus subspecies gallolyticus/fisiologia , 3',5'-AMP Cíclico Fosfodiesterases/deficiência , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Linhagem Celular , Células Epiteliais/microbiologia , Deleção de Genes , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Teste de Complementação Genética , Humanos , Camundongos , Streptococcus gallolyticus subspecies gallolyticus/química , Streptococcus gallolyticus subspecies gallolyticus/citologiaRESUMO
Here, we report a case of neonatal calf meningitis due to Streptococcus gallolyticus subsp. gallolyticus (SGG). Clinical, pathological and microbiological findings were evaluated. API Strep, 16S rRNA gene sequencing, rpoB gene sequencing and sodA gene sequencing were used for the complete identification of SGG. This is the first documented report of neonatal calf meningitis due to SGG in veterinary medicine.
Assuntos
Doenças dos Bovinos/microbiologia , Meningite/veterinária , Streptococcus gallolyticus subspecies gallolyticus/isolamento & purificação , Animais , Animais Recém-Nascidos , Técnicas Bacteriológicas/veterinária , Bovinos , Doenças dos Bovinos/patologia , Doenças dos Bovinos/fisiopatologia , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/microbiologia , Masculino , Meningite/microbiologia , Meningite/patologia , Meningite/fisiopatologiaAssuntos
Adenocarcinoma/complicações , Neoplasias do Colo/complicações , Desfibriladores Implantáveis/efeitos adversos , Endocardite Bacteriana/etiologia , Infecções Estreptocócicas/etiologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirurgia , Idoso , Antibacterianos/uso terapêutico , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/cirurgia , Colonoscopia , Remoção de Dispositivo/métodos , Dispneia , Ecocardiografia , Endocardite Bacteriana/diagnóstico por imagem , Endocardite Bacteriana/tratamento farmacológico , Febre , Humanos , Masculino , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/cirurgia , Streptococcus gallolyticus subspecies gallolyticus/isolamento & purificaçãoRESUMO
Background: Antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG) proteins, especially pilus protein Gallo2178, have been consistently associated with colorectal cancer risk. Previous case-control studies and prospective studies with up to 8 years of follow-up, however, were unable to decipher the temporality of antibody responses to SGG in the context of the long-term multistep development of colorectal cancer. In this study, we analyzed a large U.S. colorectal cancer cohort consortium with follow-up beyond 10 years for antibody responses to SGG.Methods: We applied multiplex serology to measure antibody responses to 9 SGG proteins in participants of 10 prospective U.S. cohorts (CLUE, CPSII, HPFS, MEC, NHS, NYUWHS, PHS, PLCO, SCCS, and WHI) including 4,063 incident colorectal cancer cases and 4,063 matched controls. Conditional logistic regression was used to assess whether antibody responses to SGG were associated with colorectal cancer risk, overall and by time between blood draw and diagnosis.Results: Colorectal cancer risk was increased among those with antibody responses to Gallo2178, albeit not statistically significant [OR, 1.23; 95% confidence interval (CI), 0.99-1.52]. This association was stronger for cases diagnosed <10 years after blood draw (OR, 1.40; 95% CI, 1.09-1.79), but was not found among cases diagnosed ≥10 years after blood draw (OR, 0.79; 95% CI, 0.50-1.24).Conclusions: In a large cohort consortium, we reproduced the association of antibody responses to SGG Gallo2178 with colorectal cancer risk for individuals diagnosed within 10 years after blood draw.Impact: This timing-specific finding suggests that antibody responses to SGG are associated with increased colorectal cancer risk only after tumorigenesis has begun. Cancer Epidemiol Biomarkers Prev; 27(10); 1186-94. ©2018 AACR.
Assuntos
Anticorpos Antibacterianos/sangue , Formação de Anticorpos/imunologia , Proteínas de Bactérias/imunologia , Neoplasias Colorretais/imunologia , Infecções Estreptocócicas/complicações , Streptococcus gallolyticus subspecies gallolyticus/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/imunologia , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Infecções Estreptocócicas/microbiologia , Adulto JovemAssuntos
Infecções Estreptocócicas/microbiologia , Streptococcus gallolyticus subspecies gallolyticus/fisiologia , Animais , Humanos , Infecções Estreptocócicas/transmissão , Streptococcus gallolyticus subspecies gallolyticus/genética , Streptococcus gallolyticus subspecies gallolyticus/isolamento & purificaçãoRESUMO
Streptococcus gallolyticus subsp. gallolyticus, a member of the group D streptococci, is normally found in the bovine rumen and human gut. It is an opportunistic pathogen that was recently determined to be a bacterial driver of colorectal cancer, in addition to causing other diseases, such as infective endocarditis, bacteremia, neonatal meningitis, and septicemia. As an emerging pathogen, not much is known about this bacterium, its virulence mechanisms, or its virulence regulatory pathways. Previous studies suggest that S. gallolyticus subsp. gallolyticus uses a ComRS pathway, one of many Streptococcus quorum-sensing circuitries, for competence. However, thus far, the ubiquitous ComABCDE pathway has not been studied, nor has its regulatory role in S. gallolyticus subsp. gallolyticus We therefore sought to study the S. gallolyticus subsp. gallolyticus ComABCDE quorum-sensing pathway and have identified its peptide pheromone, which is termed the competence-stimulating peptide (CSP). We further determined that this peptide regulates the production of bacteriocin-like inhibitory substances (BLISs), a phenotype that has been linked with the ComABCDE pathway in both Streptococcus pneumoniae and Streptococcus mutans Our data show that S. gallolyticus subsp. gallolyticus TX20005 produces a 21-mer CSP signal, which differs from CSP signals of other Streptococcus species in that its active form begins three residues after the double-glycine leader signal of the ComC precursor peptide. Additionally, our data suggest that this peptide might not be related to competence induction, as opposed to CSP signaling peptides in other Streptococcus species. This study provides the first evidence that S. gallolyticus subsp. gallolyticus utilizes quorum sensing to eliminate competitors, presenting a potential pathway to target this emerging human pathogen.IMPORTANCEStreptococcus gallolyticus subsp. gallolyticus is an emerging human pathogen known as a causative agent of infective endocarditis, and recently, of colorectal cancer. In this work, we revealed a functional quorum-sensing circuitry in S. gallolyticus subsp. gallolyticus, including the identification of the central signaling peptide pheromone, competence-stimulating peptide (CSP), and the regulatory role of this circuitry in the production of bacteriocin-like inhibitory substances (BLISs). This work uncovered a mechanism by which this bacterium outcompetes other bacterial species and thus provides a potential tool to study this opportunistic pathogen.
Assuntos
Proteínas de Bactérias/metabolismo , Streptococcus gallolyticus subspecies gallolyticus/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Bacteriocinas/genética , Bacteriocinas/metabolismo , Biofilmes , Regulação Bacteriana da Expressão Gênica , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Alinhamento de Sequência , Streptococcus gallolyticus subspecies gallolyticus/genética , Transformação GenéticaRESUMO
Streptococcus gallolyticus subsp. gallolyticus (Sg) has long been reported to display a strong association with colorectal cancer (CRC). It was recently demonstrated to actively promote the development of CRC, underscoring the importance of Sg in both clinical correlation and functional relevance in CRC. Here we investigated several clinical isolates of Sg in their interactions with human colon cancer cells and in mouse models. Some Sg strains were able to stimulate host cell proliferation (proliferation-promoting Sg, PP-Sg) whereas others were not (non-proliferation-promoting Sg, NP-Sg). PP-Sg strains adhered to colon cancer cells much better than NP-Sg strains, suggesting that close contact between Sg and host cells is important. In mice, PP-Sg is significantly better at colonizing the colon tissues of A/J mice compared to NP-Sg, however this difference was not observed in C57BL/6 mice, suggesting that Sg colonization of mouse colon tissues involves specific interactions between bacterial and host factors on the colonic epithelium. Finally, in an azoxymethane-induced mouse model of CRC, PP-Sg promoted tumor development whereas NP-Sg did not. These findings provide clues to the mechanism underlying the Sg-CRC association and have important implications to clinical studies that aim to correlate Sg with clinical and pathological features of CRC.
Assuntos
Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Infecções Estreptocócicas/complicações , Streptococcus gallolyticus subspecies gallolyticus/isolamento & purificação , Streptococcus gallolyticus subspecies gallolyticus/fisiologia , Animais , Adesão Celular , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Células Epiteliais/microbiologia , Células Epiteliais/fisiologia , Humanos , Camundongos , Streptococcus gallolyticus subspecies gallolyticus/patogenicidadeRESUMO
The gut microbiome is increasingly implicated in colorectal cancer (CRC) development. A subgroup of patients diagnosed with CRC show high antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG). However, it is unclear whether the association is also present pre-diagnostically. We assessed the association of antibody responses to SGG proteins in pre-diagnostic serum samples with CRC risk in a case-control study nested within a prospective cohort. Pre-diagnostic serum samples from 485 first incident CRC cases (mean time between blood draw and diagnosis 3.4 years) and 485 matched controls in the European Prospective Investigation into Nutrition and Cancer (EPIC) study were analyzed for antibody responses to 11 SGG proteins using multiplex serology. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable conditional logistic regression models. Antibody positivity for any of the 11 SGG proteins was significantly associated with CRC risk with 56% positive controls compared to 63% positive cases (OR: 1.36, 95% CI: 1.04-1.77). Positivity for two or more proteins of a previously identified SGG 6-marker panel with greater CRC-specificity was also observed among 9% of controls compared to 17% of CRC cases, corresponding to a significantly increased CRC risk (OR: 2.17, 95% CI: 1.44-3.27). In this prospective nested case-control study, we observed a positive association between antibody responses to SGG and CRC development in serum samples taken before evident disease onset. Further work is required to establish the possibly etiological significance of these observations and whether SGG serology may be applicable for CRC risk stratification.