Salpingeal infection model of Mycoplasma genitalium

描述(申请人提供)：生殖支原体是一种新发现的生殖道疾病综合征的病因，包括尿道炎、粘液脓性宫颈炎症、盆腔炎和子宫内膜炎，可能的后遗症包括不孕不育、慢性盆腔疼痛和早产。评价生殖支原体的致病机制、免疫生物学和毒力因子的研究目前正在几个实验室进行，但由于缺乏合适的动物模型而受到限制。黑猩猩不再用于实验研究，以前曾被用来证明生殖支原体致病的能力，并持续存在于这些动物的尿路、阴道、宫颈和输卵管中。虽然对其他灵长类物种的研究较少，但生殖支原体在大多数被测试物种中持续感染，产生特有的疾病，并诱导抗体反应。位于华盛顿大学的华盛顿国家灵长类动物研究中心(WaNPRC)的存在，以及Patton博士开发的输卵管口袋模型，为研究生殖支原体感染的免疫发病机制提供了一个独特的机会。Totten博士的研究证明了生殖支原体的疾病关联，抗原变异在这种微生物在受感染女性身上持续存在的能力中可能扮演的角色，以及她被证明有能力培养这种挑剔的有机体，为研究这种新生物的分子发病机制提供了必要的专业知识。因此，我们建议评估辫尾猕猴作为动物模型，以研究生殖支原体的生长、持久性和体液抗体反应；确定疾病的局部免疫生物学；并评估生殖支原体在感染期间持续存在的机制。Patton博士开发的输卵管囊袋模型成功地用于阐明沙眼衣原体感染，该模型将被用于评估生殖道支原体感染。这些研究将在未来评估宿主对感染的先天和获得性免疫反应、生殖支原体用来避免免疫反应并在体内持续存在的机制、生殖支原体感染的发病机制以及评价杀菌剂预防感染的作用。公共卫生相关性：生殖支原体是一种新发现的性传播病原体，其流行率和重要性可与沙眼衣原体和淋病奈瑟菌相媲美。人们对这种细菌引发疾病的机制知之甚少，部分原因是还没有为这种病原体开发出合适的动物模型。重要的是，这种微生物已经发展出一种潜在的抗原变异机制，这可能解释了它在感染者身上持续存在的能力，从而导致慢性感染。我们建议开发一种灵长类动物模型来研究生殖支原体感染的免疫生物学，使用在沙眼衣原体研究中非常成功的技术。这个由华盛顿国家灵长类动物研究中心(WaNPRC)开发的模型将提供一个独特的机会来研究动物和与人类疾病关系最密切的组织中生殖支原体的宿主/细菌相互作用。此外，这一模型的发展将为评估预防和治疗这种新出现的病原体的战略提供未来的机会。

DESCRIPTION (provided by applicant): Mycoplasma genitalium is a newly recognized cause of reproductive tract disease syndromes, including urethritis, mucopurulent cervicitis, pelvic inflammatory disease, and endometritis, with possible sequelae that include infertility, chronic pelvic pain, and preterm birth. Studies assessing the pathogenesis, immunobiology, and virulence factors of M. genitalium are currently being performed in several laboratories, yet are limited by the lack of an appropriate animal model. Chimpanzees, which are no longer available for experimental studies, have been previously used to demonstrate the ability of M. genitalium to cause disease and persist in the urethra, vagina, cervix, and oviducts of these animals. Although other primate species have been less extensively studied, M. genitalium has persistently infected, produced characteristic disease, and induced an antibody response in the majority of species tested. The availability of the Washington National Primate Research Center (WaNPRC) housed at the University of Washington, and the salpingeal pocket model developed by Dr. Patton, a co-investigator on this application, provides a unique opportunity to study the immunopathogenesis of M. genitalium infection. Dr. Totten's research demonstrating the disease associations of M. genitalium, the possible role of antigenic variation in the ability of this organism to persist in infected women, and her proven ability to culture this fastidious organism, provide the necessary expertise to study the molecular pathogenesis of this novel organism. We thus propose to assess the pigtailed macaque as an animal model to study the growth, persistence, and humoral antibody response to M. genitalium; determine the local immunobiology of disease; and evaluate the mechanisms used by M. genitalium to persist during infection. The salpingeal pocket model, developed by Dr. Patton and successfully employed for the elucidation of C. trachomatis infection, will be used to assess M. genitalium infection. The studies proposed herein will lead to future studies assessing the innate and adaptive host immune response to infection, the mechanisms used by M. genitalium to avoid the immune response and persist in vivo, the pathogenesis of M. genitalium infection, and the evaluation of microbicides to prevent infection. PUBLIC HEALTH RELEVANCE: Mycoplasma genitalium is a newly recognized sexually transmitted pathogen with a prevalence and significance that rivals that of Chlamydia trachomatis and Neisseria gonorrhoeae. Little is known about the mechanisms used by this bacterium to elicit disease, in part because suitable animal models have not been developed for this pathogen. Importantly, this organism has developed a potential mechanism of antigenic variation that may explain its ability to persist in infected individuals to cause chronic infections. We propose to develop a primate model to study the immunobiology of M. genitalium infection, using techniques that have been highly successful for the study of C. trachomatis. This model, developed at the Washington National Primate Research Center (WaNPRC), will provide a unique opportunity to study the host/bacterial interactions of M. genitalium in an animal and in tissues most closely related to human disease. Further, development of this model will provide future opportunity to assess strategies for prevention and treatment of this emerging pathogen.