RESUMO
BACKGROUND: Periodontal disease has a direct impact on the immune response and has been linked to several chronic diseases, including atherosclerosis and stroke. Few studies have examined the association between periodontal disease and cancer. PATIENTS AND METHODS: A total of 19 933 men reported being never smokers (of cigarette, pipes or cigars) in the Health Professionals' Follow-up Study. Periodontal disease status and teeth number were self-reported at baseline and during follow-up. All cancers were ascertained during 26 years of follow-up. Cox's proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) adjusting for risk factors. RESULTS: A 13% increase in total cancer was observed among men reporting periodontitis at baseline, and a 45% increase in risk was observed among men with advanced periodontitis (periodontitis with <17 remaining teeth). Periodontitis was not associated with prostate cancer, colorectal cancer or melanoma, the three most common cancers in this cohort of never smokers, but a 33% increase in risk was observed for smoking-related cancers (lung, bladder, oropharnygeal, esophageal, kidney, stomach and liver cancers; HR = 1.33, 95% CI 1.07-1.65). Men with advanced periodontitis had an HR of 2.57 (95% CI 1.56-4.21; P = 0.0002) for smoking-related cancers, compared with men who did not have periodontitis and had 17 teeth or more. Advanced periodontitis was associated with elevated risks of esophageal and head and neck cancers (HR = 6.29, 95% CI 2.13-18.6; based on five cases with advanced periodontitis) and bladder cancer (HR = 5.06, 95% CI 2.32-11.0; based on nine cases with advanced periodontitis). CONCLUSIONS: Advanced periodontitis was associated with a 2.5-fold increase in smoking-related cancers among never smokers. Periodontitis may impact cancer risk through system immune dysregulation. Further studies need to examine the immune impact of advanced periodontitis on cancer, especially for cancers known to be caused by smoking.
Assuntos
Neoplasias Colorretais/epidemiologia , Pessoal de Saúde , Melanoma/epidemiologia , Doenças Periodontais/epidemiologia , Neoplasias da Próstata/epidemiologia , Adulto , Idoso , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Humanos , Masculino , Melanoma/etiologia , Melanoma/patologia , Pessoa de Meia-Idade , Doenças Periodontais/complicações , Doenças Periodontais/patologia , Modelos de Riscos Proporcionais , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/patologia , Fatores de Risco , Fumantes , Fumar/epidemiologiaRESUMO
Cardiovascular disease is an inflammatory disorder characterized by the progressive formation of plaque in coronary arteries, termed atherosclerosis. It is a multifactorial disease that is one of the leading causes of death worldwide. Although a number of risk factors have been associated with disease progression, the underlying inflammatory mechanisms contributing to atherosclerosis remain to be fully delineated. Within the last decade, the potential role for infection in inflammatory plaque progression has received considerable interest. Microbial pathogens associated with periodontal disease have been of particular interest due to the high levels of bacteremia that are observed after routine dental procedures and every day oral activities, such as tooth brushing. Here, we explore the potential mechanisms that may explain how periodontal pathogens either directly or indirectly elicit immune dysregulation and consequently progressive inflammation manifested as atherosclerosis. Periodontal pathogens have been shown to contribute directly to atherosclerosis by disrupting endothelial cell function, one of the earliest indicators of cardiovascular disease. Oral infection is thought to indirectly induce elevated production of inflammatory mediators in the systemic circulation. Recently, a number of studies have been conducted focusing on how disruption of the gut microbiome influences the systemic production of proinflammatory cytokines and consequently exacerbation of inflammatory diseases such as atherosclerosis. It is clear that the immune mechanisms leading to atherosclerotic plaque progression, by oral infection, are complex. Understanding the immune pathways leading to disease progression is essential for the future development of anti-inflammatory therapies for this chronic disease.
Assuntos
Aterosclerose/imunologia , Inflamação/imunologia , Microbiota/imunologia , Doenças Periodontais/imunologia , Periodonto/imunologia , Animais , Aterosclerose/tratamento farmacológico , Progressão da Doença , Humanos , Placa Aterosclerótica/microbiologia , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVE: Periodontal disease is a highly complex chronic inflammatory disease of the oral cavity. Multiple factors influence periodontal disease, including socio-economic status, genetics and age; however, inflammation elicited by the presence of specific bacteria in the subgingival space is thought to drive the majority of soft- and hard-tissue destruction. Porphyromonas gingivalis is closely associated with periodontal disease. Toll-like receptors (TLRs) and their intracellular signaling pathways play roles in the host response to P. gingivalis. The focus of the current study was to use microarray analysis to define the contributions of the TLR adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/interleukin-1 receptor domain-containing adaptor inducing interferon-beta (TRIF), and aging, on the expression of TLR pathway-associated mRNAs in response to P. gingivalis. MATERIAL AND METHODS: Bone marrow-derived macrophages (BMØ) from wild-type (Wt), MyD88 knockout (MyD88-KO) and Trif(Lps2) [i.e. containing a point mutation in the lipopolysaccharide 2 (Lps2) gene rendering the Toll/interleukin (IL)-1 receptor domain-containing adaptor inducing interferon-beta (TRIF) protein nonfunctional] mice, at 2-and 12-mo of age, were cultured with P. gingivalis. Expression of genes in BMØ cultured with P. gingivalis was determined in comparison with expression of genes in BMØ cultured in medium only. RESULTS: Using, as criteria, a twofold increase or decrease in mRNA expression, differential expression of 32 genes was observed when Wt BMØ from 2-mo-old mice were cultured with P. gingivalis compared with the medium-only control. When compared with 2-mo-old Wt mice, 21 and 12 genes were differentially expressed (p < 0.05) as a result of the mutations in MyD88 or TRIF, respectively. The expression of five genes was significantly (p < 0.05) reduced in Wt BMØ from 12-mo-old mice compared with those from 2-mo-old mice following culture with P. gingivalis. Age also influenced the expression of genes in MyD88-KO and Trif(Lps2) mice challenged with P. gingivalis. CONCLUSIONS: Our results indicate that P. gingivalis induces differential expression of TLR pathway-associated genes, and both MyD88 and TRIF play roles in the expression of these genes. Age also played a role in the expression of TLR-associated genes following stimulation of BMØ with P. gingivalis.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Envelhecimento/genética , Fator 88 de Diferenciação Mieloide/genética , Porphyromonas gingivalis/imunologia , Transdução de Sinais/genética , Receptores Toll-Like/genética , Envelhecimento/imunologia , Animais , Células da Medula Óssea/imunologia , Células Cultivadas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Técnicas de Inativação de Genes , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Lipopolissacarídeos/genética , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Mutação Puntual/genéticaRESUMO
This report describes the cloning and sequencing of the major iron-regulated protein (termed Fbp) of Neisseria gonorrhoeae strain F62. Attempts to identify recombinants expressing the Fbp using specific antibody proved unsuccessful. Therefore, an alternative cloning strategy using oligonucleotide probes derived from NH2-terminal and tryptic fragments of this protein was used to identify short fragments of the gene. Using this methodology, the gene encoding the precursor of Fbp was cloned on three separate overlapping fragments and sequenced, and the amino acid sequence was deduced. These data were unambiguously confirmed by the known NH2-terminal amino acid sequence and were supported by the sequences from tryptic fragments that lie outside of this region. Using oligonucleotide probes, we were unable to obtain clones encoding the potential regulatory region of this protein. Therefore, the technique of inverse polymerase chain reaction was used to amplify a fragment containing an additional 200 bp. This fragment was cloned and sequenced and found to contain a consensus ribosome binding site and potential -10 and -35 sequences. Hybridization analysis of genomic DNA from gonococcal strain F62 indicated that only a single copy of the Fbp gene exists per genome. These results complement the biochemical characterization of the Fbp expressed by gonococci and further suggest that it has a role in iron-acquisition.
Assuntos
Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Bactérias , Genes Bacterianos , Ferro/metabolismo , Neisseria gonorrhoeae/genética , Sequência de Aminoácidos , Arginina , Proteínas da Membrana Bacteriana Externa/isolamento & purificação , Sequência de Bases , Clonagem Molecular , DNA Bacteriano/genética , Escherichia coli/genética , Proteínas de Ligação ao Ferro , Dados de Sequência Molecular , Peso Molecular , Hibridização de Ácido Nucleico , Sondas de Oligonucleotídeos , Mapeamento de Peptídeos , Proteínas Periplásmicas de Ligação , Plasmídeos , Proteínas Recombinantes/isolamento & purificação , Mapeamento por RestriçãoRESUMO
Several microbial pathogens can modulate the host apoptotic response to infection, which may contribute to immune evasion. Various studies have reported that infection with the sexually transmitted disease pathogen Neisseria gonorrhoeae can either inhibit or induce apoptosis. N. gonorrhoeae infection initiates at the mucosal epithelium, and in women, cells from the ectocervix and endocervix are among the first host cells encountered by this pathogen. In this study, we defined the antiapoptotic effect of N. gonorrhoeae infection in human endocervical epithelial cells (End/E6E7 cells). We first established that N. gonorrhoeae strain FA1090B failed to induce cell death in End/E6E7 cells. Subsequently, we demonstrated that stimulation with N. gonorrhoeae protected these cells from staurosporine (STS)-induced apoptosis. Importantly, only End/E6E7 cells incubated with live bacteria and in direct association with N. gonorrhoeae were protected from STS-induced apoptosis, while heat-killed and antibiotic-killed bacteria failed to induce protection. Stimulation of End/E6E7 cells with live N. gonorrhoeae induced NF-kappaB activation and resulted in increased gene expression of the NF-kappaB-regulated antiapoptotic genes bfl-1, cIAP-2, and c-FLIP. Furthermore, cIAP-2 protein levels also increased in End/E6E7 cells incubated with gonococci. Collectively, our results indicate that the antiapoptotic effect of N. gonorrhoeae in human endocervical epithelial cells results from live infection via expression of host antiapoptotic proteins. Securing an intracellular niche through the inhibition of apoptosis may be an important mechanism utilized by N. gonorrhoeae for microbial survival and immune evasion in cervical epithelial cells.
Assuntos
Apoptose , Colo do Útero/microbiologia , Proteínas Inibidoras de Apoptose/fisiologia , Neisseria gonorrhoeae/patogenicidade , Apoptose/efeitos dos fármacos , Proteína 3 com Repetições IAP de Baculovírus , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Caspase 3/fisiologia , Células Cultivadas , Colo do Útero/patologia , Feminino , Gonorreia/imunologia , Humanos , Proteínas Inibidoras de Apoptose/genética , NF-kappa B/fisiologia , Porinas/fisiologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Estaurosporina/farmacologia , Ubiquitina-Proteína LigasesRESUMO
Periodontal diseases are a group of diseases that lead to erosion of the hard and soft tissues of the periodontium, which, in severe cases, can result in tooth loss. Anecdotal clinical observations have suggested that poor oral health may be associated with poor systemic health; however, only recently have appropriate epidemiological studies been initiated, with defined clinical endpoints of periodontal disease, to address the association of periodontal disease with increased risk for cardiovascular and cerebrovascular disease. Although conflicting reports exist, these epidemiological studies support this connection. Paralleling these epidemiological studies, emerging basic scientific studies also support that infection may represent a risk factor for atherosclerosis. With P. gingivalis as a model pathogen, in vitro studies support that this organism can activate host innate immune responses associated with atherosclerosis, and in vivo studies demonstrate that this organism can accelerate atheroma deposition in animal models. In this review, we focus primarily on the basic scientific studies performed to date which support that infection with bacteria, most notably P. gingivalis, accelerates atherosclerosis. Furthermore, we attempt to bring together these studies to provide an up-to-date framework of emerging theories into the mechanisms underlying periodontal disease and increased risk for atherosclerosis, as well as identify intervention strategies to reduce the incidence of periodontal disease in humans, in an attempt to decrease risk for systemic complications of periodontal disease such as atherosclerotic cardiovascular disease.
Assuntos
Aterosclerose/imunologia , Aterosclerose/microbiologia , Imunidade Inata , Doenças Periodontais/imunologia , Porphyromonas gingivalis/patogenicidade , Animais , Aterosclerose/etiologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/microbiologia , Humanos , Mediadores da Inflamação/fisiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Doenças Periodontais/complicações , Doenças Periodontais/microbiologia , Porphyromonas gingivalis/imunologia , Transdução de Sinais , Receptores Toll-Like/imunologiaRESUMO
Pathogenic Neisseria species need to obtain iron from the host to grow in vivo. Several iron-transport systems are known, and regulation of Neisseria iron-transport genes occurs via the transcriptional regulator Fur. There is evidence that the ability to transport iron is crucial to the survival of these organisms in vivo.
Assuntos
Ferro/metabolismo , Neisseria/metabolismo , Animais , Proteínas da Membrana Bacteriana Externa/fisiologia , Sequência de Bases , Transporte Biológico , Regulação Bacteriana da Expressão Gênica , Humanos , Dados de Sequência Molecular , Neisseria/patogenicidadeRESUMO
Porphyromonas gingivalis is one of the principal pathogens in the development of adult periodontitis. Several different animal models have been used to evaluate the complex interactions between P. gingivalis and the host and these have been an important research tool for studying the pathogenesis of P. gingivalis-mediated periodontal diseases.
Assuntos
Infecções por Bacteroidaceae , Doenças Periodontais , Porphyromonas gingivalis/fisiologia , Adulto , Perda do Osso Alveolar , Animais , Infecções por Bacteroidaceae/fisiopatologia , Infecções por Bacteroidaceae/terapia , Modelos Animais de Doenças , Cães , Humanos , Doenças Periodontais/fisiopatologia , Doenças Periodontais/terapia , Periodontite/complicações , PrimatasRESUMO
Adult periodontitis is a chronic inflammatory disease that affects over 49 million people in the USA alone. Porphyromonas (formerly Bacteroides) gingivalis, a Gram-negative anaerobe, has a diverse repertoire of virulence factors that may be involved in the induction or progression of periodontitis.
Assuntos
Infecções por Bacteroidaceae/microbiologia , Gengiva/microbiologia , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Infecções por Bacteroidaceae/imunologia , Humanos , Mucosa Bucal/microbiologia , Periodontite/imunologia , Porphyromonas gingivalis/metabolismo , Virulência/genéticaRESUMO
The role of inducible nitric oxide synthase (iNOS) in bone development and bacterially induced periodontal bone loss was examined using mice with targeted mutation of the iNOS gene. Femurs of iNOS KO mice showed 30% and 9% higher bone mineral density compared to wild type (WT) at 4 and 9 weeks of age, respectively. Micro-computed tomography revealed that cortical thickness and cortical bone density is increased in the absence of iNOS, while trabecular bone thickness and bone density remains unchanged. Histochemical analysis using TRAP staining showed that osteoclast numbers are lower by 25% in iNOS KO femurs compared to WT femurs. When bone marrow cells were stimulated with M-CSF and RANKL in vitro, iNOS KO cultures developed 51% fewer TRAP-positive multinuclear cells compared to WT cultures. When similar cultures were grown on dentine discs, resorption pit area was decreased by 54% in iNOS KO cultures. Gene expression studies showed that iNOS expression is induced by M-CSF and RANKL in WT bone marrow cultures, while no iNOS transcript was detected in iNOS KO. No compensatory change was detected in the expression of neuronal or endothelial NOS isoforms. There was no difference in RANK and osteoprotegerin expression between iNOS KO and WT bone marrow cultures after M-CSF and RANKL-treatment, while Traf6 expression was significantly lower in the absence of iNOS. In the alveolar bone of the maxilla, the distance between the cementoenamel junction and the alveolar bone crest was larger in iNOS KO compared to WT mice from 6 to 14 weeks of age, indicating a developmental effect of iNOS in oral tissues. Oral administration of the periodontal pathogen Porphyromonas gingivalis caused alveolar bone loss in the maxilla of WT mice, but failed to do so in iNOS KO mice. Expression of the osteoclast marker cathepsin K was 25% lower in iNOS KO alveolar bone. These data indicate that iNOS promotes bone resorption during bone development as well as after bacterial infection, and that iNOS is an important signal for normal osteoclast differentiation.
Assuntos
Perda do Osso Alveolar/enzimologia , Perda do Osso Alveolar/microbiologia , Desenvolvimento Ósseo/fisiologia , Óxido Nítrico Sintase/fisiologia , Porphyromonas gingivalis/patogenicidade , Perda do Osso Alveolar/genética , Animais , Infecções por Bacteroidaceae/enzimologia , Infecções por Bacteroidaceae/genética , Infecções por Bacteroidaceae/microbiologia , Desenvolvimento Ósseo/genética , Células Cultivadas , Feminino , Regulação da Expressão Gênica/fisiologia , Doenças Maxilares/enzimologia , Doenças Maxilares/genética , Doenças Maxilares/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/deficiência , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo IIRESUMO
The pathogenic Neisseria and most commensal Neisseria species produce an iron-binding protein (Fbp) when grown under iron-limited conditions. In the current study, we confirmed the presence of Fbp, as well as DNA sequences homologous to the gonococcal fbp, in strains of N. gonorrhoeae, N. meningitidis, N. cinerea, N. lactamica, N. subflava, N. kochii and N. polysaccharea. The fbp genes from these strains were amplified by the polymerase chain reaction, digested with StuI or RsaI, and the restriction patterns examined. The patterns for the gonococcal and meningococcal fbp were virtually identical; however, variations were observed in the fbp sequences of the commensal Neisseria species. N. flavescens, N. mucosa, N. sicca, N. ovis and Branhamella catarrhalis, did not produce Fbp as detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and reactivity with an Fbp specific monoclonal antibody, nor did they hybridize to an fbp-specific DNA probe.
Assuntos
Proteínas de Bactérias/genética , Genes Bacterianos/genética , Variação Genética/genética , Neisseria/genética , Sequência de Aminoácidos , Anticorpos Antibacterianos , Anticorpos Monoclonais , Proteínas da Membrana Bacteriana Externa , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Sequência de Bases , Southern Blotting , Sondas de DNA , DNA Bacteriano/análise , Proteínas de Ligação ao Ferro , Dados de Sequência Molecular , Neisseria gonorrhoeae/genética , Neisseria meningitidis/genética , Proteínas Periplásmicas de Ligação , Reação em Cadeia da Polimerase , Mapeamento por Restrição , Análise de Sequência , Especificidade da EspécieRESUMO
Magainins are cationic peptides with antimicrobial activity which were originally isolated from the skin of the African clawed frog (Xenopus laevis). Several synthetic derivatives of this class of peptides were evaluated for antiviral activity against herpes simplex virus, type 1 (HSV). Some of the peptides (MSI-102, -248, -420, -499/500 combination, -591, -594, and -1251) showed significant reduction of HSV plaque-forming units. The antiviral effect was enhanced when HSV was pretreated with the peptides prior to inoculation onto Vero monolayers, suggesting a direct effect on the virion. Most of the peptides with anti-HSV activity were lysine-rich, and the addition of octanoyl groups to the peptides appeared to enhance the antiviral effect.
Assuntos
Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Chlorocebus aethiops , Herpesvirus Humano 1/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Peptídeos/química , Células Vero , Ensaio de Placa ViralRESUMO
A hallmark of infection with the gram-negative pathogen Porphyromonas gingivalis is the induction of a chronic inflammatory response. P. gingivalis induces a local chronic inflammatory response that results in oral inflammatory bone destruction, which manifests as periodontal disease. In addition to chronic inflammation at the initial site of infection, mounting evidence has accumulated supporting a role for P. gingivalis-mediated periodontal disease as a risk factor for several systemic diseases including, diabetes, preterm birth, stroke, and atherosclerotic cardiovascular disease. A growing number of in vitro studies have demonstrated that P. gingivalis infection stimulates cell activation commensurate with expected responses paralleling inflammatory atherosclerotic-type responses. Furthermore, various mouse models have been used to examine the ability of P. gingivalis to stimulate chronic inflammatory plaque accumulation and recent studies have pointed to a pivotal role for innate immune signaling via the Toll-like receptors in the chronic inflammation associated with P. gingivalis infection. In this review we discuss the pathogen and host cell specificity of these responses and discuss possible mechanisms by which this oral pathogen can induce and maintain a chronic state of inflammation at sites distant from oral infection.
Assuntos
Aterosclerose/etiologia , Infecções por Bacteroidaceae/imunologia , Periodontite Crônica/complicações , Infecção Focal Dentária/imunologia , Infecção Focal Dentária/microbiologia , Porphyromonas gingivalis/imunologia , Animais , Aterosclerose/imunologia , Aterosclerose/microbiologia , Periodontite Crônica/imunologia , Periodontite Crônica/microbiologia , Modelos Animais de Doenças , Endotélio Vascular/microbiologia , Células Espumosas/imunologia , Humanos , Imunidade Celular , Imunidade Inata , Camundongos , Especificidade de Órgãos , Receptores Toll-Like/imunologiaAssuntos
Bactérias/patogenicidade , Infecções Bacterianas , Cultura em Câmaras de Difusão , Modelos Animais de Doenças , Interações Hospedeiro-Parasita , Próteses e Implantes , Animais , Bactérias/imunologia , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Cobaias , Inflamação , Camundongos , Coelhos , Especificidade da Espécie , VirulênciaAssuntos
Endometriose/patologia , Neoplasias/patologia , Coristoma/patologia , Endométrio/patologia , Feminino , Menopausa , ParidadeAssuntos
Amniocentese , Adulto , Ensaios Clínicos como Assunto , Feminino , Humanos , Itália , Diagnóstico Pré-Natal/métodosRESUMO
As with other pathogens, a requirement for the in vivo growth of Porphyromonas gingivalis is that the organism must be capable of obtaining iron from the host. The ability to utilize hemin and hemin-containing compounds for nutritional iron has been documented for several pathogenic bacteria, including P. gingivalis; however, the mechanisms involved in hemin uptake are poorly defined. I have determined that P. gingivalis transports the entire hemin moiety into the cell by an energy-dependent mechanism and that the binding and accumulation of hemin are induced by growth of cultures in the presence of hemin. A model of hemin transport in P. gingivalis consistent with these results is presented. I have also found that, in P. gingivalis, hemin regulates the expression of several putative virulence factors; this in turn results in the increased virulence potential of P. gingivalis as assessed in an animal model. Regulation of hemin-responsive genes in P. gingivalis may occur by a negative regulator, as has been described in other pathogenic organisms.