Mycoplasma genitalium variation in longitudinally infected men

纵向感染男性的生殖支原体变异

• 批准号: 8721850
• 负责人: PATRICIA A TOTTEN
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721850
• 关键词: Adherence; Amino Acids; Animal Model; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Formation; Antigenic Variation; Appearance; Archives; Automobile Driving; Bacteria; Bacterial Adhesins; Biological; Biological Assay; Cell Wall; Cell division; Cells; Cervical; Cervicitis; Chronic Disease; Clinical; Code; Collection; Complement; Complex; Development; Disease; Endometritis; Enrollment; Environment; Epitopes; Etiology; Evolution; Funding; Genes; Genetic Recombination; Genital system; Genome; Goals; Human; Immune; Immune Targeting; Immune response; Immunoglobulin Variable Region; In Vitro; Infection; Infertility; Inflammatory Response; Intervention; Laboratories; Longitudinal Studies; Measures; Mediating; Membrane Proteins; Methods; Modeling; Molecular; Morphology; Mycoplasma genitalium; Natural Resistance; Nature; Oligopeptides; Organelles; Organism; Oryctolagus cuniculus; Pathogenesis; Patients; Pelvic Inflammatory Disease; Premature Birth; Prevention strategy; Proteins; Resistance; Role; Serum; Shapes; Specimen; Surface; Testing; Time; United States National Institutes of Health; Urethritis; Urine; Vagina; Variant; Visit; Woman; base; cell motility; flasks; in vivo; innovation; killings; men; novel; pathogen; public health relevance; reproductive; research study; treatment strategy; treatment trial

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.

描述（由申请人提供）：生殖支原体 (MG) 是男性尿道炎的病因，并且因其在女性宫颈炎、子宫内膜炎、盆腔炎、输卵管因素不孕和早产中的病因作用而得到越来越多的认识。不幸的是，这种细菌对细胞壁靶向抗生素以及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。尽管在感染过程中诱导了炎症反应和特异性抗体，但男性和女性的 MG 感染可能会持续数月至数年。我们和其他人假设，这种持久性是基于 MG 通过位于其复杂而独特的末端细胞器中的两种表面蛋白 MgpB 和 MgpC 的抗原变异来逃避宿主免疫反应的能力。支持这一假设的是，我们发现编码这些蛋白质的相邻基因 mgpB 和 mgpC 的变异在体内广泛存在，并且在宫颈/阴道感染中随着时间的推移而演变。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时间匹配的患者分离株的基因变异和抗原选择的作用来检验这一假设。我们最近由美国国立卫生研究院资助的生殖支原体治疗试验给了我们这样的机会。在这项已完成的试验中，确定了生殖支原体感染的男性，并要求他们每隔三周返回一次，进行三到四次访问，同时收集血清及其生殖支原体菌株 进行培养和表征。这些实验是前所未有的，因为巡回研究将使用最近的临床分离株，而不是实验室适应的菌株。因此，我们建议 1) 表征整个纵向研究中不同时间点 mgpB 序列变异的演变，2) 将 mgpB 中特定可变序列的清除与受感染男性中这些序列的抗体的发展相关联，以及 3)确定这些变异序列的抗体是否增强补体介导的对生殖支原体的杀伤。这项研究的创新之处在于，它经济地使用了一组极其有价值且特征明确的患者标本来评估基因变异对这种新识别病原体持久性的作用。这项研究的意义在于，它将部分揭示这种新认识的生殖器病原体的免疫逃避机制。我们关注这种尚未充分研究的细菌的免疫发病机制的潜在影响是巨大的，因为可以确定干预和治疗的新靶标。