Project 2 - Regulation of the T-cell Memory Response in Chlamydia Genital Tract

性传播感染(STI)沙眼衣原体感染是两种疾病中最常见的细菌性STI 对美国和全世界来说，这是一个重大的公共卫生问题。目前，还没有 可靠预测潜在破坏性衣原体相关生殖并发症的生物标志物，如 如不孕症和异位妊娠；因此，开发衣原体疫苗是高度优先的。这个 衣原体感染或疫苗接种后“保护性免疫”的传统定义包括减少 细菌脱落，缩短感染持续时间，减少慢性组织损伤。然而， 保护性免疫的免疫学相关性不太明确，通常包括世代 免疫球蛋白抗体和强健的CD4+Th1反应，尽管后者也与病理有关 并且可能不足以作为免疫效果的单次读出。这个项目的总体目标是 确定有助于衣原体有效产生的免疫学和细胞反应 小鼠特定的免疫记忆。我们假设CD4+中枢和效应器记忆 感染或免疫后引起的表型是感染或免疫的关键决定因素 保护性免疫和/或病理，以及作为必然结果，改变IL-23/Th17反应可能导致 CD4+T细胞记忆反应不足。利用一系列体内实验在已建立的 小鼠模型，我们的假设将通过以下具体目标进行验证：1)表征细胞和 与保护性CD4+记忆性T细胞反应发展相关的免疫学反应 在衣原体生殖道感染之后。2)评估IL-23/Th17的贡献 对鼠疫杆菌产生有效的CD4+T细胞中枢和效应器记忆反应的反应 生殖道感染。3)确定用被杀死的生物进行免疫是否会引起不同的记忆反应 而不是自然感染。从拟议研究中获得的信息将推动项目负责人的 近期和长期的职业目标，以扩大她的技术和分析研究技能，制定 衣原体感染后不良疾病结局的生物标记物，并将基础研究结果翻译成 免疫学实验室对性传播感染的临床相关预防和干预策略。《项目》 Leader将把热情的指导与众多的机构资源相结合，以实现她的目标 成为一名独立的研究员，在生殖道粘膜领域拥有既定的科学地位 免疫学。

Sexually transmitted infections (STI) with Chlamydia trachomatis are the most common bacterial STI in both the United States and worldwide and represent a significant public health concern. At present, there are no biomarkers to reliably predict potentially devastating Chlamydia-associated reproductive complications, such as infertility and ectopic pregnancy; therefore, development of a chlamydial vaccine is a high priority. The traditional definition of "protective immunity" following chlamydial infection or vaccination includes reduced bacterial shedding, shortened duration of infection, and diminished chronic tissue damage. However, the immunologic correlates of protective immunity are less well-defined and have generally included generation of IgG antibody and a robust CD4+ Th1 response although the latter has also been implicated in pathology and may not be adequate as a single read-out for immunologic efficacy. The overall goal of this project is to define the immunologic and cellular responses that contribute to effective generation of Chlamydia muridarum-specific immunologic memory. We hypothesize that the CD4+ central and effector memory phenotype elicited following C. muridarum Infection or immunization is a critical determinant of protective immunity and/or pathology and, as a corollary, that altered IL-23/Th17 responses may result in inadequate CD4+ T-cell memory responses. Employing a series of in vivo experiments in an established mouse model, our hypothesis will be tested by the following Specific Aims: 1) Characterize the cellular and immunologic responses associated with the development of protective CD4+ memory T-cell responses following Chlamydia muridarum genital tract infection. 2) Evaluate the contribution of the IL-23/Th17 response in generation of effective CD4+ T-cell central and effector memory responses to C. muridarum genital tract infection. 3) Determine if immunization with killed organisms elicits a different memory response than natural infection. Information gained from the proposed studies will advance the Project Leader's immediate and long-term career objectives to expand her technical and analytical research skills, develop biomarkers for adverse disease outcomes following Chlamydia STI, and translate findings in the basic immunology laboratory into clinically relevant prevention and intervention strategies for STI. The Project Leader will integrate enthusiastic mentorship with numerous institutional resources to reach her goal of becoming an independent investigator with an established scientific niche in genital tract mucosal immunology.