Mycoplasma genitalium variation in longitudinally infected men

描述（由申请人提供）：生殖道支原体（MG）是男性尿道炎的一种病因，其在宫颈炎、子宫内膜炎、盆腔炎、输卵管性不孕和女性早产中的病因作用越来越被认识。不幸的是，这种细菌对细胞壁靶向抗生素和许多目前用于治疗原发性疾病和可能的严重生殖道疾病后遗症的抗生素具有耐药性。MG感染可在男性和女性中持续数月至数年，尽管在感染期间会诱导炎症反应和特异性抗体。我们和其他人假设，这种持久性是基于MG逃避宿主免疫反应的能力，通过其复杂和独特的末端细胞器中两种表面蛋白MgpB和MgpC的抗原变异。为了支持这一假设，我们已经证明编码这些蛋白质的邻近基因mgpB和mgpC的变异在体内广泛存在，并且随着时间的推移在宫颈/阴道感染中进化。然而，到目前为止，我们还无法通过评估感染诱导的抗体对当代和暂时匹配的患者分离株的基因变异和抗原选择的作用来验证这一假设。我们最近由美国国立卫生研究院资助的生殖器支原体治疗试验给了我们这样一个机会。在这个完整的试验中，生殖器支原体感染的男性被确定，并被要求每隔三周进行三到四次访问，在此期间收集血清和他们的生殖器支原体菌株

DESCRIPTION (provided by applicant): Mycoplasma genitalium (MG) is a cause of urethritis in men and is becoming increasingly recognized for its etiologic role in cervicitis, endometritis, pelvic inflammatory disease, tubal factor infertility, and preterm birth in women. Unfortunately, this bacterium is resistant to cell wall-targeting antibiotics and to many of the antibiotics curretly used to treat primary disease and possible serious reproductive tract disease sequelae. MG infection may persist in humans for months to years in both men and women despite the induction of an inflammatory response and specific antibodies during infection. We and others have hypothesized that this persistence is based on the ability of MG to evade the host immune response by antigenic variation in two of its surface proteins, MgpB and MgpC located in its complex and unique terminal organelle. Supporting this hypothesis, we have shown that variation in mgpB and mgpC, the adjacent genes encoding these proteins, is extensive both in vivo and evolves over time in cervical/vaginal infections. However, up to this point, we have not been able to test this hypothesis by assessing the role of antibodies induced by infection on gene variation and antigenic selection of contemporary and temporally matched patient isolates. Our recent NIH-funded treatment trial for M. genitalium has given us such an opportunity. In this completed trial, M. genitalium infected men were identified and asked to return at three week intervals for three to four visits at which time sera was collected and their M. genitalium strains were cultured and characterized. These experiments are unprecedented because recent clinical isolates, not laboratory-adapted strains will be used in tour study. Thus we propose to 1) characterize the evolution of mgpB sequence variation of at different time points throughout the longitudinal study, 2) correlate the clearance of specific variable sequences in mgpB with the development of antibodies to these sequences in the infected men, and 3) determine if the antibodies to these variant sequences enhance complement-mediated killing of M. genitalium. This study is innovative in its economical use of an extremely valuable and well-characterized set of patient specimens to assess the role of gene variation on persistence of this newly recognized pathogen. This study is significant in that it will reveal, in part, the mechanisms of immune evasion in this newly recognized genital pathogen. The potential impact of our focus on the immunopathogenesis of this understudied bacterium is great in that novel targets for intervention and treatment may be identified.