Proj. 4-The Genetic Variation of Innate Immune Genes w/Oral Manifestations of HIV

项目。

• 批准号: 8377539
• 负责人: Peter A Zimmerman
• 金额: $ 31.42万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377539
• 关键词: 11p; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Africa; African American; Agonist; Aphthous Stomatitis; Area; Autoimmune Diseases; Bacteria; CD4 Positive T Lymphocytes; CXCR4 gene; Candidiasis; Cause of Death; Cells; Cessation of life; Chemotaxis; Child; Communicable Diseases; Complex; Complication; Cytomegalovirus; DEFB1 gene; Defensins; Development; Disease; Disease Progression; Disease susceptibility; Economic Factors; Effectiveness; Environment; Epidemic; Epithelial; Epithelial Cells; Ethnic Origin; Family; Family member; Frequencies; Gene Cluster; Gene Dosage; Gene Family; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; HIV; HIV Infections; HIV Seropositivity; Hairy Leukoplakia; Haplotypes; Highly Active Antiretroviral Therapy; Host Defense; Human; Human Papillomavirus; Immune; Immune System Diseases; Immune response; Immune system; Immunosuppression; Incidence; Individual; Infection; Inflammation Mediators; Inflammatory; Kaposi Sarcoma; Maintenance; Mediating; Microbe; Mothers; Mucosal Immunity; Natural Immunity; Opportunistic Infections; Oral; Oral Manifestations; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Outcome; Pathology; Patients; Peptides; Periodontitis; Play; Population; Predisposition; Process; Property; Race; Risk; Role; Signal Transduction; Simplexvirus; Single Nucleotide Polymorphism; Stomatitis; Structure; Surface; TLR1 gene; Tissues; Toll-like receptors; Up-Regulation; Variant; Vertical Disease Transmission; Viral; Virus; antimicrobial; beta-Defensins; fungus; member; microbial; oral infection; oral lesion; oral wart; outcome forecast; receptor; response; socioeconomics; treatment response

Oral manifestations of HIV have been documented since the initial presentation of the HIV/AIDS epidemic of the 80's. The most common oral complication was candidiasis, and was associated with a reduction in CD4+T cells. Oral candidal infection was a hallmark indicator of immune dysfunction. The increased incidence of opportunistic infections was related to immune suppression as evidenced by a reduction in number and functional activity of CD4 + T cells. The frequency and type of oral complication has changed since the initial description of the 80s. With the initiation of HAART therapies the constellation of oral manifestations has changed. The incidence of HPV associated warts and severe aphthous ulcer stomatitis has increased, whereas oral candidal infection and oral hairy leukoplakia has declined. In addition, not all patients develop these pathologies. The variation in disease presentation and concomitant response to therapy may be related to genetic predisposition of innate immune genes and variation in epithelial barrier function. Innate immunity is increasingly being recognized as playing a critical role in host defense against infectious diseases, including HIV. The defensin peptides have antimicrobial properties and are major protective components of the epithelial mucosal barrier. Genetic variation of the defensin genes in the form of SNPs and CNVs has been shown to be associated with disease susceptibility. Toll-like receptors (TLRs), a family of evolutionary conserved receptors on host cells including human oral epithelial cells, recognize specific microbial structures, leading to the up-regulation of inflammatory mediators and recruitment of inflammatory cells. Multiple interactions of microbes and host tissues and secreted antimicrobial molecules such as beta-defensins are involved in the maintenance of the homeostatic environment of the healthy mouth, however, little is known about the role of TLRs in this process or the impact of HIV disease on these processes. Polymorphisms in the TLR family and the common adaptor Tirap/Mal have been associated with many human infectious and autoimmune diseases. We hypothesize that host variation in TLRs and their signaling components contribute to the variability in oral infections seen in HIV disease by altering host/microbe interactions at the mucosal surface. We will decipher the relationship of genetic variations in both the defensin gene cluster and toll-like receptors TLR1 and 2 with oral manifestations of HIV/AIDS. We will define and correlate specific complex haplotypes with the frequency and occurrence of oral lesions in the HIV population. We hypothesize that susceptibility, prognosis, and outcome of HIV are associated with genetic variations in the defensin gene cluster. This same variation also may be associated with the development of oral complications following HIV infection

自#年首次出现艾滋病毒/艾滋病流行以来，记录了艾滋病毒的口腔表现。 80年代的S。最常见的口腔并发症是念珠菌病，并与减少 CD4+T细胞。口腔念珠菌感染是免疫功能障碍的标志性指标。增加的 机会性感染的发生率与免疫抑制有关，这一点从以下方面得到了证明 CD4+T细胞的数量和功能活性。口腔并发症的频率和类型发生了变化 从80年代的最初描述开始。随着HAART疗法的开始，口腔星座 表现形式发生了变化。人乳头瘤病毒相关性尖锐湿疣和严重口腔溃疡的发生率 口腔念珠菌感染和口腔毛状白斑有所下降。此外，并不是所有 患者会患上这些病症。疾病表现的变化和伴随的反应 治疗可能与先天免疫基因的遗传易感性和上皮屏障的变异有关 功能。越来越多的人认识到先天免疫在宿主防御中发挥着关键作用。 传染病，包括艾滋病毒。防御素多肽具有抗菌特性，是主要的 上皮粘膜屏障的保护性成分。形式中防御素基因的遗传变异 SNPs和CNV的数量已被证明与疾病易感性有关。Toll样受体(TLR)， 包括人类口腔上皮细胞在内的宿主细胞上的一组进化保守的受体，识别 特定的微生物结构，导致炎症介质上调和招募 炎性细胞。微生物与宿主组织的多重相互作用及分泌的抗菌分子 如β-防御素参与维持健康人群的动态平衡环境 然而，对于TLRs在这一过程中的作用或HIV疾病对这些细胞的影响，人们知之甚少 流程。TLR家族和共同的适配器TIRAP/MAL的多态与 许多人类传染病和自身免疫性疾病。我们假设TLR和它们的寄主变异 信号成分通过改变HIV疾病中可见的口腔感染的可变性 宿主/微生物在粘膜表面的相互作用。我们将破译基因变异之间的关系 防御素基因簇和Toll样受体TLR1和Toll样受体2与HIV/AIDS的口腔表现有关。我们 将定义特定的复杂单倍型并将其与口腔病变的频率和发生情况相关联 艾滋病病毒感染者。我们假设艾滋病毒的易感性、预后和结局与 防御素基因簇的遗传变异。这种相同的变化也可能与 HIV感染后口腔并发症的研究进展