Immunomodulation and Vaccine Optimization against Chlamydia

描述(申请人提供)：沙眼衣原体是一种主要的感染性病原体，在世界范围内引起性传播疾病(STD)。2007年，美国疾病预防和控制中心报告了1108,374例衣原体感染病例。女性的并发症包括盆腔炎、异位妊娠和非自愿输卵管因素不孕。最近的研究发现，通过抗菌治疗减少感染会增加人类的再感染率，实际上可能会加剧生殖道内的病理。这些发现突显了预防生殖器衣原体感染的有效疫苗的必要性。衣原体疫苗工作中的一个主要挑战是了解控制保护性反应和致病性反应的免疫调节机制。这项建议的主要目的是确定IL-10缺陷的DC产生的免疫调节分子在促进针对生殖器衣原体感染的保护性免疫反应和消除与感染相关的免疫病理中的作用。对这些分子作用机制的了解可能导致在设计针对衣原体的药物和有效疫苗时有针对性的免疫调节策略。我们将通过两个具体目标来实现这些目标。目的：探讨衣原体致敏的IL-10缺陷树突状细胞中上调的α-烯醇化酶和脂肪酸结合蛋白在生殖器衣原体感染保护性免疫应答中的作用。我们的工作假设是，衣原体致敏的IL-10缺陷DC中上调的分子在DC快速成熟和Th1细胞激活中起着一定的作用。研究建议有：a)。探讨α-烯醇化酶和脂肪酸结合蛋白在DC体外获得成熟标志和增强APC功能中的作用。b)。探讨α-烯醇化酶和脂肪酸结合蛋白在体内外免疫调节作用中的细胞信号机制。目的：研究衣原体致敏的IL-10KO BMDCs中表达下调的凋亡相关斑点样蛋白(ASC)在体内、外抗衣原体感染过程中的免疫保护作用。我们的工作假设是，衣原体致病的IL-10缺陷树突状细胞中下调的分子在病理性免疫反应中起着一定的作用。研究建议有：a)。探讨ASC DC获得成熟标志物和增强APC功能的作用及其在衣原体致输卵管病变和不孕症中的作用。B)探讨ASC在DC免疫调节功能中的作用。这些研究的结果将有助于开发针对衣原体的药物和疫苗，这将对控制和预防生殖器衣原体感染和后遗症具有重要意义。 公共卫生相关性：这项建议的主要目标是确定IL-10缺陷的DC产生的免疫调节分子在促进针对生殖器衣原体感染的保护性免疫反应和消除与感染相关的免疫病理中的作用。

DESCRIPTION (provided by applicant): Chlamydia trachomatis is a major infectious bacterial agent that causes sexually transmitted disease (STD) worldwide. In the United States 1,108,374 Chlamydia infections were reported to the Centers for Disease Prevention and Control in 2007. Complications in women include pelvic inflammatory disease, ectopic pregnancy and involuntary tubal factor infertility. Recent studies have discovered that decreasing the infection through antimicrobial treatment increases the re-infection rate in humans and may actually exacerbate the pathology within the reproductive tract. These findings highlight the need for an effective vaccine against genital Chlamydia infection. A major challenge in Chlamydia vaccine efforts is to understand the immune regulatory mechanisms governing the protective versus the pathogenic responses. The main objective of this proposal is to define the roles of immunomodulatory molecules produced by IL-10 deficient DCs in promoting a protective immune response against genital Chlamydia infection and eliminating the immunopathology associated with the infection. The knowledge of the mechanism of action of such molecules could lead to targeted immunomodulatory strategies in designing drugs and efficacious vaccines against Chlamydia. We will accomplish these objectives using 2 specific aims. Aim 1: To define the role of alpha-enolase and fatty acid-binding protein up-regulated in Chlamydia-pulsed IL-10 deficient DCs in the protective immune response against genital Chlamydia infection. Our working hypothesis is that molecules up-regulated in Chlamydia-pulsed IL-10 deficient DCs play a rule in rapid DC maturation and Th1 cell activation. Study proposal are; a). To investigate the role of alpha- enolase and fatty acid-binding protein in DC acquisition of maturation markers and enhanced APC function in vitro. b). To investigate the cell signaling mechanism of immunestimulatory action of alpha-enolase and fatty acid-binding protein in vitro and in vivo. Aim 2: To define the role of apoptosis-associated speck-like protein containing a CARD (ASC) down regulated in Chlamydia-pulsed IL-10KO BMDCs in protecting against the pathological immune responses during a Chlamydia infection in vivo and in vitro. Our working hypothesis is that molecules down-regulated in Chlamydia-pulsed IL-10 deficient DCs play a rule in pathological immune responses. Study proposal are; a). To investigate of the role of ASC DC acquisition of maturation markers and enhanced APC function and the pathogeneses of Chlamydia induced tube pathology and infertility. b) To investigate the role of ASC in the immunoregulatory function of DCs. Results from these studies will aid in the development of drugs and vaccines against Chlamydia, which will have significant implications for controlling and preventing genital Chlamydia infections and sequelae. PUBLIC HEALTH RELEVANCE: The main objective of this proposal is to define the roles of immunomodulatory molecules produced by IL-10 deficient DCs in promoting a protective immune response against genital Chlamydia infection and eliminating the immunopathology associated with the infection.