The Atlantic Coast Sexually Transmitted Infection Cooperative Research Center (AC

大西洋海岸性传播感染合作研究中心（AC

• 批准号: 8769562
• 负责人: Ann E. Jerse
• 金额: $ 123.1万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769562
• 关键词: Accounting; Address; Adherence; Affect; Animal Model; Antibiotic Resistance; Antibiotics; Antigen-Presenting Cells; Antigenic Variation; Antigens; Area; Bacteria; Basic Science; Binding; Biological Assay; Biological Markers; Biology; CD4 Positive T Lymphocytes; Candy; Carcinoembryonic Antigen; Ceftriaxone; Cell Wall; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Cervix Uteri; Chelating Agents; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Chlamydial pneumonia; Clinical; Clinical Sciences; Commit; Conjunctivitis; Counseling; Data; Dendritic Cells; Development; Diagnostic; Disease; Ecology; Ectopic Pregnancy; Epigenetic Process; Evolution; Failure to Thrive; Frequencies; Genetic; Genital system; Genitourinary system; Goals; Gonorrhea; HIV; Health; Histone Deacetylase Inhibitor; Human; Immune; Immune response; Immune system; Immunity; Immunobiology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Incidence; Individual; Infection; Infertility; Inflammation; Integration Host Factors; Intervention; Iron; Knowledge; Lead; Life Style; Low Birth Weight Infant; Measures; Mediating; Membrane; Microscopy; Modeling; Mothers; Mus; Mutation; Neisseria gonorrhoeae; Neonatal; Nutritional Support; Organism; Pathogenesis; Pathway interactions; Pelvic Inflammatory Disease; Peptidoglycan; Personal Satisfaction; Predisposition; Premature Rupture Fetal Membranes; Prevalence; Prevention strategy; Preventive; Proteome; Public Health; Reporting; Reproductive Health; Research; Research Personnel; Resistance; Risk; Role; Safe Sex; Sexual Partners; Sexually Transmitted Diseases; Signal Transduction; System; T-Lymphocyte; Testing; Therapeutic; Transferrin; Transgenic Mice; Translational Research; Urethra; Vaccines; Vagina; Vesicle; Vision; Woman; Women' s Health; Work; adaptive immunity; base; chronic pelvic pain; design; disorder prevention; effective therapy; experience; extracellular; fitness; gonorrhea vaccine; improved; in vivo; innovation; lymphocyte proliferation; meetings; microbial; mouse model; neonate; novel; pathogen; perforin 2; product development; prototype; public health relevance; receptor vaccine; reproductive hormone; resistant strain; response; tissue culture; tool; transmission process; treatment strategy; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): The proposed Atlantic Coast (AC) STI CRC is a highly integrated, multidisciplined alliance of experienced investigators who are committed to advancing basic and translational science in the area of Neisseria gonorrhoeae (Ng), Chlamydia trachomatis (Ct) and Ng/Ct infections that will further our understanding of the pathogenesis of these sexually transmitted infections and lead to the development of new interventions. To meet these goals, we will address the following four programmatic specific aims. Aim 1 is to define the immunobiology of Ng and Ng/Ct co-infection with respect to mechanisms of Ng-mediated immunosuppression and the mechanisms by which Ng and Ct evade or interact with effectors of the innate defense. Two novel Ng immunosuppressive pathways that interfere with dendritic cell (DC) function will be characterized. The hypothesis that these Ng pathways affect host responses to Chlamydia will also be tested. A vaginal proteome analysis will be performed using mouse models of single and dual infection to identify novel effectors that may limit or enhance infection and to assess the influence of reproductive hormones on the expression of host factors. We will also investigate the role of perforin-2, a membrane-bound pore-forming effector, in the intracellular biology of Ng, Ct and Ng/Chlamydia at the cellular level and during experimental murine infection. Aim 2 is to develop tissue culture systems, improved animal models, and immunological systems for studying Ng/Ct confection and to accelerate product development. Tissue culture systems designed to promote Ng invasion through two distinct pathways and sophisticated microscopy will be utilized to examine the intracellular biology of Ng/Ct coinfected cells. Improved mouse models will be established using human transferrin-supplemented mice that are transgenic for the human carcinoembryonic antigen-related cellular adherence molecule (hCEACAM-1); these models will be used to identify potential biomarkers that can discriminate single and dual infections. To facilitate studies on the immunobiology of co-infection, in vitro, ex vivo and in vivo assays will be developed to examine the effect of Ng on DC-directed anti-Cm responses. Aim 3 is to understand the genetic basis of the spread of antibiotic resistant gonorrhea. The effect of ceftriaxone resistance determinants on microbial fitness in vitro and in vivo will be tested and compensatory mutations that restore fitness will be identified. Aim 4 is to develop a gonorrhea vaccine and novel therapies effective against both gonorrhea and Chlamydia infections. A promising Ng Tf receptor vaccine will be developed and the effect of a pre-existing Chlamydia infection on the efficacy of this vaccine will be assessed. Iron-chelators will be tested as a nutritional therapy and a prototype histone deacetylase inhibitor will be tested as a potentially effective epigenetic therapy that induces the expression f innate effectors and suppresses pathogen-induced inflammation.

描述（由申请人提供）：拟议的大西洋海岸（AC）STI CRC是一个高度整合，多学科的经验研究者的联盟，他们致力于在淋病Neisseria（NG）（NG）（NG），chlamydia tarachomatis（CT）和NG/CT感染的理解中推进基本和转化科学，并将其视为这些疾病的发展范围。新干预措施。 为了实现这些目标，我们将解决以下四个程序特定目标。 目的1是根据NG介导的免疫抑制的机制定义NG和NG/CT共感染的免疫生物学以及NG和CT逃避或与先天防御效应的相互作用或相互作用的机制。 将表征两个干扰树突细胞（DC）功能的新型NG免疫抑制途径。 这些NG途径影响宿主对衣原体的反应的假设也将进行测试。 将使用单个和双感染的小鼠模型进行阴道蛋白质组分析，以鉴定可能限制或增强感染并评估生殖激素对宿主因子表达的影响的新型效应子。 我们还将研究Puldorin-2（一种膜结合的孔形成效应子）在细胞，CT和NG/CHMAMYDIA在细胞水平和实验鼠感染期间的细胞内生物学中的作用。 目的2是开发组织培养系统，改进的动物模型以及用于研究NG/CT糖果和加速产品开发的免疫系统。组织培养系统旨在通过两种不同的途径促进NG侵袭，并且将利用复杂的显微镜检查NG/CT共感染细胞的细胞内生物学。改进的小鼠模型将使用人类转铁蛋白补充的小鼠建立，这些小鼠是人类癌症抗原相关的细胞依从性分子（HCEACAM-1）的转基因；这些模型将用于识别可以区分单一感染和双重感染的潜在生物标志物。 为了促进有关共感染免疫生物学的研究，将开发体内，体内和体内测定，以检查NG对NG对 直流定向的抗CM响应。 目的3是了解抗生素耐药性淋病传播的遗传基础。 头孢曲松抗性决定因素对体外和体内微生物适应性的影响将进行测试，并且恢复适应性的代偿突变将是 确定。 目标4是开发淋病疫苗和新型疗法，可对淋病和衣原体感染有效。 将开发出有希望的NG TF受体疫苗，并将评估预先存在的衣原体感染对该疫苗功效的影响。铁切剂将作为一种营养疗法进行测试，原型组蛋白脱乙酰基酶抑制剂将被测试为一种潜在的有效表观遗传疗法，可诱导f先天效应子并抑制病原体诱导的炎症。