EFFICACY OF MICROBICIDES IN CHLAMYDIA TRACHOMATIS

众所周知，生殖器沙眼衣原体 D-K 血清型是美国流行性传播疾病 (STD) 的罪魁祸首，估计每年有 400 万例病例。衣原体疾病可能是隐匿性的，它们构成了重要的初级、二级和三级卫生保健问题，其中妇女承受着特殊的负担，因为她们增加了不良生殖后果的风险。显然，迫切需要安全、有效、女性控制的外用杀菌剂来帮助预防和控制性病。我们之前的研究表明，在已经感染了沙眼衣原体血清型 E 的人类上皮细胞中，杀菌剂 C31G 能够进入衣原体包涵体，从而对衣原体造成破坏；此外，包涵体膜完整性的改变会导致衣原体LPS的胞吐作用增加，但不会增加热休克蛋白60的胞吐作用。因此，在具体目标1中，我们设计了一个共培养模型系统，以确定暴露于C31G的衣原体感染的HeLa细胞的炎症反应细胞迁移（PMN）是否受到调节。我在好时医学院的同事已经证明，除了单纯疱疹病毒 (HSV) 和艾滋病毒之外，烷基硫酸盐对于杀死乳头瘤病毒也非常有效。因此，在具体目标 2 中，我们将评估单独使用新型外用杀菌剂候选物以及与 C31G 和烷基硫酸盐联合使用对沙眼衣原体和 HSV 双重感染的 HeLa 细胞的作用。最后，我们将使用衣原体感染的猪模型来确定在不同的激素状态（增殖和分泌）下衣原体感染的杀菌剂干预如何改变。

It is well recognized that genital Chlamydia trachomatis serovars D-K are responsible for epidemic sexually transmitted diseases (STDs) in the USA, with an estimated annual 4 million cases. Chlamydial diseases can be insidious and they constitute significant primary, secondary and tertiary health care concerns in which women bear a special burden because of their increased risk of adverse reproductive consequences. Clearly, safe, effective, female-controlled topical microbicides are urgently need to help prevent and control STDs. Our previous studies showed that in human epithelial cells already infected with C, trachomatis serovar E, the microbicide C31G gains access to the chlamydial inclusions causing destruction to chlamydiae; in addition, the alteration in inclusion membrane integrity results in increased exocytosis of chlamydial LPS but not heat shock protein 60. Thus, in Specific Aim 1, we have devised a co-culture model system to determine if there is modulation of inflammatory response cell migration (PMN) to chlamydiae-infected HeLa cells exposed to C31G. My colleagues at Hershey Medical School have shown that alkyl sulfates are quite effective in killing papillomavirus, in addition to herpes simplex (HSV) and HIV. So, in Specific Aim 2, we will evaluate the action of the new topical microbicide candidate alone and in combination with C31G and alkyl sulfates on HeLa cells doubly infected with C. trachomatis and HSV. Finally, we shall use a pig model of chlamydial infection to determine or how microbicide intervention of chlamydial infection is altered in the different hormonal states (proliferative and secretory).