Toll-Like Receptors and Microbicides

Toll 样受体和杀菌剂

• 批准号: 7111630
• 负责人: RICHARD B PYLES
• 金额: $ 34.95万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7111630
• 关键词: Chlamydia trachomatis; antiinfective agents; cervix; clinical research; cooperative study; epithelium; herpes simplex virus 2; human tissue; laboratory mouse; microorganism disease chemotherapy; mucosal immunity; nonhuman therapy evaluation; receptor expression; sexually transmitted diseases; stimulant /agonist; tissue /cell culture; toll like receptor; topical drug application; vagina

Innate immune responses are the first line of defense against sexually transmitted diseases (STDs). Initiation of the innate response is based upon recognition of pathogen-associated molecular patterns by host proteins known as toll-like receptors (TLRs). TLR agonists have been identified and have been utilized for modulation of immune responses in humans in the context of vaccine adjuvants. In this project, we propose to test the hypothesis that TLR agonists will prove to be a novel class of topical microbicides providing protection against STDs. Topical microbicides are products designed to protect against STDs. Used vaginally or rectally, microbicides offer women the advantage that they may be "female-controlled". The term microbicide implies that the product kills microorganisms; this is somewhat misleading since microbicides may work in a variety of ways including disrupting the pathogen's membrane or envelope, blocking the receptor-ligand interactions essential for infectivity, inhibiting the intra- or extra-cellular replication of the pathogen, or by altering the vaginal environment or enhancing local immune responses to reduce susceptibility. As proof of concept, we have established the utility of a TLR9 agonist as a microbicide that is effective against HSV-2 genital infections in mice and guinea pig models. This microbicide candidate was effective when applied as a single intravaginal dose within the time frame of 2d prior through 6h after vaginal challenge with HSV-2. To extend our findings and test our hypothesis, in Aim 1 we will determine the typical pattern of TLR gene expression in human vaginal and cervical epithelial cells and select a set of TLR agonists that target the commonly expressed TLRs that then will be assessed for activity in primary cultures of these cells against HSV-2 and C. trachomatis infection. TLR agonists will be prioritized for evaluation based on the in vitro results and then will be evaluated for microbicide potential in mouse models of HSV-2 and C. trachomatis vaginal infections in Aim 2. Those compounds that show greatest microbicide potential will be evaluated mechanistically in Aim 3. Completion of the studies will provide substantial information about the innate immune responses of the vaginal mucosa and will identify TLR agonist microbicide candidates.

先天性免疫反应是防止性传播疾病(STD)的第一道防线。 天然应答的启动是基于被称为Toll样受体(TLRs)的宿主蛋白对病原体相关分子模式的识别。TLR激动剂已被确定，并已被用于在疫苗佐剂的背景下调节人类的免疫反应。在这个项目中，我们建议检验这样一个假设，即TLR激动剂将被证明是一种新型的局部杀微生物剂，提供对待性传播疾病的保护。局部杀微生物剂是旨在防止性传播疾病的产品。经阴道或直肠使用的杀微生物剂为女性提供了一个优势，即它们可能是“女性控制的”。 杀微生物剂一词意味着产品会杀死微生物；这有些误导，因为杀菌剂可能以各种方式起作用，包括破坏病原体的膜或包膜，阻断感染性所必需的受体-配体相互作用，抑制病原体的细胞内或细胞外复制，或通过改变阴道环境或增强局部免疫反应来降低敏感性。作为概念的证明，我们已经确定了TLR9激动剂作为一种杀微生物剂的用途，该杀菌剂在小鼠和豚鼠模型中对HSV-2生殖器感染有效。这种候选杀微生物剂在用HSV-2阴道攻击前2d至6h内单次阴道内给药时有效。为了扩展我们的发现并验证我们的假设，在目标1中，我们将确定TLR基因在人类阴道和宫颈上皮细胞中的典型表达模式，并选择一组针对通常表达的TLR的激动剂，然后评估这些细胞在原代培养中对抗HSV-2和沙眼衣原体感染的活性。TLR激动剂将根据体外结果优先进行评估，然后在目标2中的HSV-2和沙眼衣原体阴道感染小鼠模型中评估杀微生物剂的潜力。那些显示出最大杀菌潜力的化合物将在目标3中进行机械评估。研究的完成将提供关于阴道粘膜先天免疫反应的大量信息，并将确定TLR激动剂的候选杀微生物剂。