探讨淋球菌抑制树突状细胞功能及降低HIV-1 CD8 T 细胞记忆反应的机理

Infection with N. gonorrhoeae can trigger an intense local inflammatory response at the site of infection, yet there is little specific immune response or development of immune memory. Gonococcal surface epitopes are known to undergo antigenic variation; however, this is unlikely to explain the weak immune response to infection due to the fact that individuals can be re-infected by the same serotype. While the expression of Opa （the colony opacity-associated） alleles is randomly phase-variable and can turn on and off independently, Opa-negative variants are rarely found in clinical samples obtained from men and women, indicating that Opa plays a significant role in the pathogenesis of N. gonorrhoeae. Previous studies have demonstrated that Opa proteins on the N. gonorrhoeae surface can bind human carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) on CD4+ T cells to suppress T cell activation and proliferation. In addition, N. gonorrhoeae is associated with impaired HIV-1 (human immunodeficiency virus type 1)-specific cytotoxic T-lymphocyte (CTL) responses and with transient increases in plasma viremia in HIV-1-infected patients, indicating that N. gonorrhoeae can also subvert immune responses to co-pathogens. Since dendritic cells (DCs) are professional antigen presenting cells that play a key role in the induction of an adaptive immune response, we therefore propose to investigate the effects of N. gonorrhoeae Opa proteins on human DC activation and function. We also propose to study whether DCs infected with N. gonorrhoeae expressing Opa variants reduce their capacity in inducing HIV-1-specific CTL response. We have five specific aims:1) Analysis of CEACAM1 expression by immature and mature monocyte-derived dendritic cells (MDDCs); 2) Interaction binding and internalization of iMDDCs with N. gonorrhoeae expressing Opa variants; 3) Effects of N. gonorrhoeae expressing Opa variants on MDDCs' maturation; 4) Effects of N. gonorrhoeae expressing Opa variants on MDDC-mediated allogeneic mixed lymphocyte proliferation; 5) Effects of N. gonorrhoeae infection on HIV-1-specific CTL memory response. The results from our study will provide a better understanding of the absence of effective immune memory responses to gonorrhea infection, allowing gonococcal persistence in high-risk core groups of sexually active men and women. It may also contribute to the heightened transmission of HIV-1 apparent in co-infected individuals, setting the stage for a dangerous liaison between two major sexually transmitted pathogens.

淋球菌感染能引起强烈的局部炎症反应，但不产生或仅产生微弱的免疫保护反应，且能扰乱机体对共同感染的其它病原体的免疫应答。以往研究提示，淋球菌可能通过其Opa蛋白与免疫细胞表面的癌胚抗原相关细胞黏附分子(CEACAM)相互作用、抑制T细胞的活化和增殖，但相应的机制尚不清楚。我们的前期研究也表明，成熟与未成熟MDDCs(monocyte-drived Dcs)相比CEACAM1表达显著上调，淋球菌与iMDDCs结合依赖于Opa与CEACAM1的相互作用，淋球菌Opa异变体与MDDCs相互作用可降低同种异型混合淋巴细胞的增殖反应。本课题试图阐明表达不同Opa异变体的淋球菌对树突状细胞成熟活化和功能的影响及其机制，以及淋球菌感染对HIV-1特异性CTL记忆应答的干扰作用及其分子机制。因此，该项研究将有助于揭示淋菌感染导致免疫应答缺失的分子机制，并促进淋球菌感染以及其它病原体共同感染的有效防治。

淋球菌感染能引起强烈的局部炎症反应，但不产生或仅产生微弱的免疫保护反应，且能扰乱机体对共同感染的其它病原体的免疫应答。以往研究提示，淋球菌可能通过其Opa 蛋白与免疫细胞表面的癌胚抗原相关细胞黏附分子(CEACAM)相互作用、抑制T 细胞的活化和增殖，但相应的机制尚不清楚。我们的前期研究也表明，成熟与未成熟MDDCs(monocyte-drived Dcs)相比CEACAM1 表达显著上调，淋球菌与iMDDCs 结合依赖于Opa 与CEACAM1 的相互作用，淋球菌Opa 异变体与MDDCs 相互作用可降低同种异型混合淋巴细胞的增殖反应。本课题试图阐明表达不同Opa 异变体的淋球菌对树突状细胞成熟活化和功能的影响及其机制，以及淋球菌感染对HIV-1 特异性CTL 记忆应答的干扰作用及其分子机制。因此，该项研究将有助于揭示淋菌感染导致免疫应答缺失的分子机制，并促进淋球菌感染以及其它病原体共同感染的有效防治。