STUDIES WITH ANIMAL MODELS OF SEXUALLY TRANSMITTED DISEASES

局部杀微生物剂的概念很有吸引力--这是一种安全有效的女性控制产品，目的是在阴道内使用，旨在保护女性免染性传播疾病(STD)。随着越来越多的化合物被确定为潜在的杀微生物剂，重要的是制定确定最有希望的候选化合物的战略。项目1和2以及核心B中的研究将确定对重要的STD病原体具有出色的体外抗菌活性和出色的安全性的化合物。在这个项目中，我们将使用特征明确的生殖道感染动物模型来研究选定的候选杀微生物剂的有效性和安全性。在具体目标1中，我们将使用单纯疱疹病毒(HSV)和衣原体生殖道感染的小鼠和豚鼠模型来评估杀菌剂限制宫颈-阴道感染的能力，并在生殖器疱疹模型的情况下预防疾病。使用这些模型，我们还将探索杀菌剂是否可以防止病原体传播到重要的次级部位：对于HSV，传播到感觉神经节神经元；对于衣原体，传播到上生殖道。这些模型允许我们探索有希望的化合物在性交前或性交后使用的有效性。在具体目标2中，我们将使用动物模型来研究体液(例如血液或精液)的存在如何影响杀微生物剂的效果。我们将通过确定杀微生物剂是否可以减少宫颈阴道分泌物中的微生物数量，以及开发和使用新的STD小鼠传播模型，来探索杀微生物剂是否可以减少受感染的女性向易感男性伴侣传播STD。在具体目标3中，我们将探讨杀菌剂是否具有免疫毒性这一重要的安全问题。使用标准的免疫学方法评估生殖道免疫，我们将探索候选杀微生物剂影响已知在保护女性生殖道免受性传播病原体感染方面至关重要的先天免疫反应的潜力。这些研究将提供关于候选杀微生物剂在保护雌性动物免受两种重要的STD病原体感染方面的体内有效性的重要信息。这些实验还将探索杀微生物剂是否会影响女性向男性传播性病的问题，并调查杀微生物剂是否对女性生殖道具有免疫毒性这一重要问题。总而言之，这些研究将描述杀菌剂的体内行为，并确定具有突出疗效和安全性的化合物。总体而言，这项研究预计将产生信息，使杀菌剂的合理优先次序在临床试验中得到进一步评估。

The concept of the topical microbicide is attractive - a safe and effective, female-controlled product destined for intravaginal use and intended to protect women from acquiring sexually transmitted diseases (STDs). With an increasing number of compounds identified as potential microbicides it is important to develop strategies for identifying the most promising candidates. Studies in Projects 1 and 2 and Core B will identify compounds with excellent in vitro antimicrobial activity against important STD pathogens and outstanding safety profiles. In this project we will investigate the efficacy and safety of selected candidate microbicides using well-characterized animal model of genital tract infection. In specific aim 1 we will use mouse and guinea pig models of herpes simplex virus (HSV) and chlamydial genital tract infection to assess the ability of microbicides to limit cervico-vaginal infection and, in the case of the genital herpes models, prevent disease. Using these models we will also explore whether microbicides can prevent spread of the pathogen to important secondary sites: for HSV, to sensory ganglion neurons; and for chlamydia, to the upper genital tract. These models allow us explore the effectiveness of promising compounds for either pre- or post-coital use. In specific aim 2 we will use animal models to examine how microbicides efficacy can be affected by the presence of body fluids (e.g. blood or semen). We will explore whether microbicides might reduce STD transmission from infected women to susceptible male partners by determining whether microbicides can reduce the amount of organism present in cervico-vaginal secretions and by developing and using new murine models of STD transmission. In specific aim 3 we will explore the important safety issue of whether microbicides are immunotoxic. Using standard immunological methods to assess genital tract immunity, we will explore the potential of candidate microbicides to impact innate immune responses known to be important in protecting the female genital tract against infection by sexually transmitted pathogens. These studies will provide important information regarding the in vivo effectiveness of candidate microbicides in protecting female animals against two important STD pathogens. These experiments will also explore the issue of whether microbicides can impact female to male STD transmission and investigate the important question of whether microbicides are immunotoxic to the female genital tract. Collectively, theses studies will characterize the in vivo behavior of microbicides and identify compounds with outstanding efficacy and safety profiles. Overall, this research is expected to yield information that will allow for the rational prioritization of microbicides for further evaluation in clinical trials.