Tobacco-induced alterations to P. gingivalis-host interactions

烟草引起的牙龈卟啉单胞菌与宿主相互作用的改变

• 批准号: 8460435
• 负责人: David A Scott
• 金额: $ 35.64万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460435
• 关键词: Anabolism; Antibodies; Antigens; Area; Back; Bacteria; Bacterial Proteins; Cells; Cellular Structures; Characteristics; Chronic; Chronic Obstructive Airway Disease; Clinical; Communicable Diseases; Conditioned Culture Media; Coronary Arteriosclerosis; Cytokine Suppression; Data; Dental; Diabetes Mellitus; Disease; Economic Burden; Exhibits; Exposure to; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genome; Genomics; Goals; Gram-Negative Anaerobic Bacteria; Health Care Costs; Human; IS Elements; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Investigation; Lipid A; Lung diseases; Membrane; Membrane Proteins; Microarray Analysis; Microbial Biofilms; Modeling; Molecular; Operon; Organism; Pathogenesis; Patients; Periodontitis; Persons; Phenotype; Physiological; Play; Pneumonia; Polysaccharides; Population; Porphyromonas gingivalis; Predisposition; Proteins; Refractory; Relative (related person); Reporter Genes; Risk; Rodent Model; Role; Severities; Smoke; Smoker; Smoking; Specificity; Stress; Stroke; Structure; Surface; Systemic disease; TNF gene; Testing; Tissues; Tobacco; Tobacco smoke; Tooth structure; Transcript; Transposase; United States; Vascular Diseases; Virulence; capsule; cigarette smoke-induced; cigarette smoking; fimbria; in vivo; insight; microbial; monocyte; neutrophil; non-smoker; novel; pathogen; public health relevance; response; tobacco exposure; trait

DESCRIPTION (provided by applicant): Periodontitis is a destructive, infectious disease that has been associated with multiple fatal and debilitating chronic systemic diseases and consumes billions of dollars in health costs annually in the US. Tobacco smokers exhibit increased susceptibility to periodontitis; are more likely to be infected with the key periodontal pathogen Porphyromonas gingivalis; and to harbor higher numbers of this bacterial species relative to non-smokers. Despite this, smokers consistently exhibit reduced clinical inflammation. We show that the pro-inflammatory response of purified human monocytes is significantly suppressed when P. gingivalis is exposed to cigarette smoke extracts (CSE) and that the inflammation inducing potential of P. gingivalis is restored when cells are sub-cultured back into fresh medium without CSE. However, the influence of tobacco on the regulation of genes encoding P. gingivalis virulence determinants is essentially unknown. We hypothesize that CSE represents an environmental stress and that P. gingivalis responds by altering gene expression to adapt to this stress. We believe that this adaptive response may involve the induction of stress-related genes, virulence determinants and alterations of bacterial surface components. We also hypothesize that such cigarette smoke-induced physiological changes in P. gingivalis will include altered activities of genes encoding key pathogen recognition determinants, which will explain the reduced inflammatory response of smoke-exposed P. gingivalis. It is our aim to identify, isolate and test CSE-altered gene products in a primary human monocyte model of inflammation. Preliminary data generated through transcriptome analyses and the structural characterization of several microbial determinants are strongly supportive of our hypotheses. We have identified several genes, gene products, and bacterial structures that are dysregulated on CSE exposure that may play pivotal roles in the engagement of the innate immune system by P. gingivalis. These include fimbrial proteins, LPS, major outer membrane antigens, and other P. gingivalis components of known inflammatory potential, such as dnaJ, grpE and ragA. These studies represent a novel area of investigation and will provide some of the first information illustrating how P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights into disease pathogenesis in smokers. Thus, these studies will break new ground and provide the foundation for future studies that will elucidate mechanisms explaining how tobacco influences pathogen-host response interactions.

描述（由申请人提供）：牙周炎是一种具有破坏性的传染病，与多种致命和衰弱的慢性全身性疾病有关，每年在美国消耗数十亿美元的健康成本。吸烟者表现出对牙周炎的敏感性提高。更可能被关键的牙周病原体卟啉单胞菌感染；并具有相对于非吸烟者的大量这种细菌物种。尽管如此，吸烟者始终表现出减少的临床炎症。我们表明，当牙龈疟原虫暴露于香烟烟雾提取物（CSE）时，纯化的人单核细胞的促炎反应被显着抑制，并且当将细胞恢复到新鲜的培养基中时，恢复了牙龈疟原虫的炎症潜力没有CSE。但是，烟草对编码牙龈疟原虫毒力决定因素的基因调节的影响本质上是未知的。 我们假设CSE代表环境应力，并且牙龈疟原虫通过改变基因表达以适应这种应激而做出反应。我们认为，这种适应性反应可能涉及与应激相关基因的诱导，毒力决定因素和细菌表面成分的改变。我们还假设，这种香烟烟雾诱导的牙龈疟原虫的生理变化将包括编码关键病原体识别决定因素的基因的改变，这将解释烟雾暴露的牙龈疟原虫的炎症反应减少。我们的目的是在原代的人类炎症模型中识别，分离和测试改变CSE的基因产物。 通过转录组分析产生的初步数据和几种微生物决定因素的结构表征强烈支持我们的假设。我们已经确定了几种基因，基因产物和细菌结构，这些基因在CSE暴露中失调，这些基因可能在gingivalis的先天免疫系统参与中起关键作用。这些包括纤维化蛋白，LPS，主要的外膜抗原和其他已知炎症潜能的牙龈疟原虫成分，例如DNAJ，GRPE和RAGA。 这些研究代表了一个新的调查领域，并将提供一些第一个信息，说明牙龈疟原虫在分子水平上如何对香烟烟雾做出反应，并可能提供对吸烟者疾病发病机理的独特见解。因此，这些研究将破坏新的基础，并为将来的研究奠定基础，以阐明烟草如何影响病原体宿主反应相互作用的机制。