Toll-Like Receptors and Microbicides

Toll 样受体和杀菌剂

• 批准号: 7679394
• 负责人: RICHARD B PYLES
• 金额: $ 41.37万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679394
• 关键词: Acute; Address; Agonist; Animals; Antibodies; Biostatistics Core; Cavia; Cell membrane; Cells; Cervical; Chemicals; Chlamydia trachomatis; Class; Collaborations; Complex; Data; Data Analyses; Development; Dose; Double-Stranded RNA; Environment; Epidemic; Epithelial Cells; Epithelium; Evaluation; Failure; Female; Flagellin; Gene Expression; Genital system; Goals; Human; Human Herpesvirus 2; Immune response; In Vitro; Infection; Infection prevention; Integral Membrane Protein; Intravaginal Administration; Laboratories; Lead; Ligands; Lipids; Lipoproteins; Local Microbicides; Lung; Membrane; Modeling; Molecular; Mucous Membrane; Mus; Natural Immunity; Nucleic Acids; Oligonucleotides; Organism; Pattern; Phagocytes; Play; Predisposition; Prevention; Primary Cell Cultures; Process; Production; Proteins; Receptor Gene; Reporting; Resistance; Resource Sharing; Role; Sexually Transmitted Diseases; Signal Pathway; Structure; Testing; Time; Tissues; Toll-like receptors; Urinary tract; Vaccine Adjuvant; Vagina; Vaginal Route of Drug Administration; Woman; Work; base; cell type; chemokine; concept; cytokine; design; ds-DNA; genital infection; insight; killings; men; microbicide; microorganism; mouse model; novel; pathogen; prototype; receptor; receptor expression; response; success; viral DNA

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.

先天免疫反应是抵抗性传播疾病（STD）的第一道防线。 先天性应答的启动是基于被称为toll样受体（TLR）的宿主蛋白对病原体相关分子模式的识别。TLR激动剂已被鉴定并已在疫苗佐剂的情况下用于调节人的免疫应答。在这个项目中，我们建议测试的假设，TLR激动剂将被证明是一种新型的局部杀微生物剂提供保护，防止性病。局部杀微生物剂是旨在预防性病的产品。用于阴道或直肠的杀微生物剂为妇女提供了一个优势，即它们可能是"女性控制的"。 术语杀微生物剂意味着该产品杀死微生物;这有点误导，因为杀微生物剂可能以多种方式起作用，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易感性。作为概念证明，我们已经建立了TLR9激动剂作为杀微生物剂的效用，其在小鼠和豚鼠模型中有效对抗HSV-2生殖器感染。该杀微生物剂候选物在用HSV-2阴道激发后2天至6小时的时间范围内作为单次阴道内剂量施用时有效。为了扩展我们的发现并检验我们的假设，在目标1中，我们将确定人阴道和宫颈上皮细胞中TLR基因表达的典型模式，并选择一组靶向通常表达的TLR的TLR激动剂，然后评估这些细胞的原代培养物中抗HSV-2和C的活性。沙眼感染TLR激动剂将根据体外结果优先进行评价，然后在HSV-2和C小鼠模型中评价杀微生物剂潜力。目的2.沙眼阴道感染。目标3将对那些显示出最大杀微生物潜力的化合物进行机理评价。这些研究的完成将提供有关阴道粘膜先天免疫应答的大量信息，并将鉴定TLR激动剂杀微生物剂候选物。