Immunomodulation and Vaccine Optimization against Chlamydia

描述（由申请人提供）：沙眼衣原体是一种主要的传染性细菌，在世界范围内引起性传播疾病（STD）。在美国，2007年向疾病预防和控制中心报告了1，108，374例衣原体感染。妇女的并发症包括盆腔炎、异位妊娠和非自愿输卵管因素不孕症。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。这些发现强调了对生殖器衣原体感染的有效疫苗的需要。衣原体疫苗工作的一个主要挑战是了解免疫调节机制的保护性与致病性反应。本提案的主要目的是确定由IL-10缺陷型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应答和消除与感染相关的免疫病理学中的作用。这些分子的作用机制的知识可能会导致有针对性的免疫调节策略，在设计药物和有效的疫苗对衣原体。我们将通过两个具体目标来实现这些目标。目标1：目的探讨衣原体致敏的IL-10缺陷型DC中α-烯醇化酶和脂肪酸结合蛋白表达上调在生殖道衣原体感染保护性免疫应答中的作用。我们的工作假设是，在衣原体脉冲IL-10缺陷DC中上调的分子在DC快速成熟和Th 1细胞活化中起作用。研究建议如下：（a）。探讨α-烯醇化酶和脂肪酸结合蛋白在体外培养的DC获得成熟标志物和增强APC功能中的作用。B）。目的：研究α-烯醇化酶和脂肪酸结合蛋白免疫调节作用的细胞信号转导机制。目标二：目的明确衣原体致敏IL-10 KO BMDCs中表达下调的CARD相关斑点样蛋白（ASC）在体内和体外衣原体感染过程中对病理性免疫应答的保护作用。我们的工作假设是，在衣原体脉冲IL-10缺陷的DC中下调的分子在病理免疫应答中起作用。研究建议如下：（a）。探讨ASC DC获得成熟标志物和APC功能增强在衣原体致输卵管病变和不孕中的作用。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及其后遗症产生重大影响。 公共卫生相关性：本提案的主要目的是确定由IL-10缺陷型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应答和消除与感染相关的免疫病理学中的作用。

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.