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: 8657377
• 负责人: David A Scott
• 金额: $ 37.13万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657377
• 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(申请人提供)：牙周炎是一种破坏性的传染病，与多种致命性和衰弱的慢性系统性疾病有关，在美国每年消耗数十亿美元的医疗费用。吸烟者对牙周炎的易感性更高；更有可能感染牙周关键病原体牙龈卟啉单胞菌；与不吸烟者相比，这种细菌的数量更多。尽管如此，吸烟者的临床炎症反应一直在减少。我们发现，当香烟烟雾提取物(CSE)暴露于纯化的人单核细胞时，Pggivalis的促炎反应明显受到抑制，当细胞传回到没有CSE的新鲜培养液中时，Pggivalis的炎症诱导潜力恢复。然而，烟草对牙龈假单胞菌毒力决定因素编码基因调控的影响基本上是未知的。我们假设CSE代表一种环境压力，牙龈假单胞菌通过改变基因表达来适应这种压力。我们认为，这种适应性反应可能涉及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假单胞菌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活性改变，这将解释烟雾暴露的牙龈假单胞菌炎症反应减弱的原因。我们的目标是在原代人类单核细胞炎症模型中识别、分离和测试CSE改变的基因产物。通过转录组分析产生的初步数据和几个微生物决定因素的结构特征有力地支持了我们的假设。我们已经确定了几个在CSE暴露中调节失调的基因、基因产物和细菌结构，这些基因、基因产物和细菌结构可能在牙龈假单胞菌参与天然免疫系统的过程中发挥关键作用。这些包括菌毛蛋白、脂多糖、主要外膜抗原和其他已知具有炎症潜在性的牙龈假单胞菌成分，如DNAJ、GRPE和RAGA。这些研究代表了一个新的研究领域，将提供一些第一批信息，说明牙龈假单胞菌如何在分子水平上对香烟烟雾做出反应，并可能为吸烟者的疾病发病机制提供独特的见解。因此，这些研究将开辟新的领域，并为未来的研究提供基础，这些研究将阐明烟草如何影响病原体-宿主反应相互作用的机制。

项目成果

Tobacco smoke augments Porphyromonas gingivalis-Streptococcus gordonii biofilm formation.

• DOI: 10.1371/journal.pone.0027386
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bagaitkar J;Daep CA;Patel CK;Renaud DE;Demuth DR;Scott DA
• 通讯作者: Scott DA

Tobacco use increases susceptibility to bacterial infection.

• DOI: 10.1186/1617-9625-4-12
• 发表时间: 2008-12-18
• 期刊: Tobacco induced diseases
• 影响因子: 3.7
• 作者: Bagaitkar J;Demuth DR;Scott DA
• 通讯作者: Scott DA

Cigarette smoke-exposed neutrophils die unconventionally but are rapidly phagocytosed by macrophages.

• DOI: 10.1038/cddis.2011.13
• 发表时间: 2011-03-17
• 期刊: Cell death & disease
• 影响因子: 9