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: 9316484
• 负责人: Ann E. Jerse
• 金额: $ 146.28万
• 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/9316484
• 关键词: Address; Adherence; Affect; Animal Model; Antibiotic Resistance; Antibiotics; Antigen-Presenting Cells; Antigenic Variation; Antigens; Area; Bacteria; Basic Science; Biological Assay; Biological Models; 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; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Chlamydial pneumonia; Clinical; Clinical Sciences; Conjunctivitis; Data; Dendritic Cells; Development; Diagnostic; Disease; Ecology; Ectopic Pregnancy; Epigenetic Process; Evolution; Failure to Thrive; Frequencies; Genetic; Genitourinary system; Goals; Gonorrhea; HIV; Health; Histone Deacetylase Inhibitor; Human; Immune Evasion; Immune response; Immune system; Immunity; Immunobiology; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Incidence; Individual; Infection; Infertility; Inflammation; Information Sciences; Integration Host Factors; Intervention; Iron Chelating Agents; 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; Predisposition; Premature Rupture Fetal Membranes; Prevalence; Prevention strategy; Preventive measure; Proteome; Public Health; Reporting; Reproductive Health; Research; Research Personnel; Resistance; Risk; Role; Safe Sex; Sex Counseling; Sexual Partners; Sexually Transmitted Diseases; Signal Transduction; System; T-Lymphocyte; Testing; Therapeutic; Transferrin; Transgenic Mice; Translational Research; Urethra; Vaccine Therapy; Vaccines; Vagina; Vesicle; Vision; Woman; Women' s Health; Work; adaptive immune response; adaptive immunity; chronic pelvic pain; co-infection; design; disorder prevention; experience; extracellular; fitness; gonorrhea vaccine; improved; in vivo; innovation; lymphocyte proliferation; microbial; mouse model; neonate; novel; novel therapeutics; pathogen; perforin 2; potential biomarker; product development; prototype; public health relevance; receptor vaccine; reproductive hormone; reproductive tract; 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 是一个由经验丰富的研究人员组成的高度整合的多学科联盟，致力于推进淋病奈瑟菌 (Ng)、沙眼衣原体 (Ct) 领域的基础和转化科学和 Ng/Ct 感染，这将进一步我们对这些性传播感染发病机制的了解，并导致新干预措施的开发。 为了实现这些目标，我们将实现以下四个具体目标。 目标 1 是定义 Ng 和 Ng/Ct 共感染的免疫生物学，涉及 Ng 介导的免疫抑制机制以及 Ng 和 Ct 逃避先天防御效应器或与先天防御效应器相互作用的机制。 将描述干扰树突状细胞 (DC) 功能的两种新型 Ng 免疫抑制途径。 这些 Ng 途径影响宿主对衣原体反应的假设也将得到检验。 将使用单次和双重感染的小鼠模型进行阴道蛋白质组分析，以确定可能限制或增强感染的新效应物，并评估生殖激素对宿主因子表达的影响。 我们还将研究穿孔素-2（一种膜结合的成孔效应物）在细胞水平上和实验性小鼠感染过程中 Ng、Ct 和 Ng/衣原体的细胞内生物学中的作用。 目标 2 是开发组织培养系统、改进的动物模型和免疫系统，用于研究 Ng/Ct 糖果并加速产品开发。旨在通过两种不同途径促进 Ng 侵袭的组织培养系统和复杂的显微镜将用于检查 Ng/Ct 共感染细胞的细胞内生物学。将使用补充人转铁蛋白的小鼠建立改进的小鼠模型，这些小鼠是人癌胚抗原相关细胞粘附分子（hCEACAM-1）的转基因小鼠；这些模型将用于识别可以区分单一和双重感染的潜在生物标志物。 为了促进共感染免疫生物学的研究，将开发体外、离体和体内测定法来检查 Ng 对 DC 定向的抗 Cm 反应。 目标 3 是了解抗生素耐药性淋病传播的遗传基础。 将测试头孢曲松耐药性决定因素对体外和体内微生物适应性的影响，并将恢复适应性的补偿突变 确定。 目标 4 是开发针对淋病和衣原体感染有效的淋病疫苗和新疗法。 将开发一种有前景的 Ng Tf 受体疫苗，并将评估先前存在的衣原体感染对该疫苗功效的影响。铁螯合剂将作为营养疗法进行测试，原型组蛋白脱乙酰酶抑制剂将作为潜在有效的表观遗传疗法进行测试，该疗法可诱导先天效应子的表达并抑制病原体诱导的炎症。