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、由女性控制的产品，用于阴道内使用，旨在保护妇女免受性传播疾病的感染。随着越来越多的化合物被确定为潜在的杀微生物剂，制定确定最有希望的候选化合物的策略是很重要的。项目1、项目2和项目B的研究将鉴定出对重要性病病原体具有良好体外抗菌活性和突出安全性的化合物。在本项目中，我们将使用具有良好特征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，我们将使用小鼠和豚鼠单纯疱疹病毒（HSV）和衣原体生殖道感染模型来评估杀微生物剂限制宫颈阴道感染的能力，以及在生殖器疱疹模型的情况下预防疾病的能力。使用这些模型，我们还将探索杀微生物剂是否可以阻止病原体传播到重要的次要部位：对于HSV，传播到感觉神经节神经元；对于衣原体，是上生殖道。这些模型使我们能够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检查体液（如血液或精液）的存在如何影响杀微生物剂的功效。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存在的生物体数量，以及开发和使用新的STD传播小鼠模型，来探索杀微生物剂是否可以减少感染性病的女性向易感男性伴侣传播性病。在具体目标3中，我们将探讨杀微生物剂是否具有免疫毒性这一重要的安全性问题。使用标准的免疫学方法来评估生殖道免疫，我们将探索候选杀微生物剂影响先天免疫反应的潜力，已知先天免疫反应在保护女性生殖道免受性传播病原体感染方面很重要。这些研究将为候选杀微生物剂保护雌性动物免受两种重要性病病原体的体内有效性提供重要信息。这些实验还将探讨杀微生物剂是否会影响女性对男性的性病传播，并研究杀微生物剂是否对女性生殖道具有免疫毒性的重要问题。总的来说，这些研究将描述杀微生物剂的体内行为，并确定具有突出疗效和安全性的化合物。总的来说，这项研究预计将产生的信息，将允许合理优先考虑杀菌剂在临床试验中进一步评估。

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.