EFFICACY OF MICROBICIDES IN CHLAMYDIA TRACHOMATIS

众所周知，生殖器沙眼衣原体血清型D-K是美国流行性性传播疾病（std）的罪魁祸首，估计每年有400万例病例。衣原体疾病可能是潜伏的，它们构成了重大的初级、二级和三级保健问题，妇女因其不利生殖后果的风险增加而承受着特殊的负担。显然，迫切需要安全、有效、女性控制的局部杀微生物剂来帮助预防和控制性传播疾病。我们之前的研究表明，在已经感染C，血清沙眼原体E的人上皮细胞中，杀微生物剂C31G可以进入衣原体包涵体，造成衣原体的破坏；此外，包合膜完整性的改变导致衣原体LPS的胞吐增加，而不是热休克蛋白60的胞吐增加。因此，在Specific Aim 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细胞是否存在炎症反应细胞迁移（PMN）的调节。我在好时医学院的同事已经证明，烷基硫酸盐在杀死乳头瘤病毒、单纯疱疹病毒（HSV）和艾滋病毒方面非常有效。因此，在特异性目标2中，我们将评估新的局部杀菌剂候选物单独使用以及与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，我们将使用猪衣原体感染模型来确定杀微生物剂对衣原体感染的干预在不同的激素状态（增殖和分泌）下是如何改变的。

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).