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）：支原体生殖器（MG）是男性尿道炎的原因，并且由于其在宫颈炎，子宫内膜炎，骨盆炎性疾病，管状因子不育症和女性早产而在宫颈炎，子宫内膜炎，骨盆炎性疾病，骨盆炎性疾病中的病因作用越来越受到认可。不幸的是，该细菌对细胞壁靶向抗生素具有抗药性，以及用于治疗原发性疾病和可能严重生殖道疾病后遗症的许多抗生素。尽管在感染过程中诱导了炎症反应和特定抗体，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在其复杂且独特的末端细胞器中通过抗原变异MGPB和MGPC中抗原变异来逃避宿主免疫反应的能力。在支持这一假设的情况下，我们已经表明，MGPB和MGPC的变化（编码这些蛋白质的相邻基因）在体内和随着时间的流逝都广泛地在宫颈/阴道感染中变化。但是，到目前为止，我们无法通过评估感染对当代和时间匹配的患者分离株的基因变异和抗原选择诱导的抗体的作用来检验这一假设。我们最近针对生殖器的NIH资助的治疗试验为我们提供了这样的机会。在这项完整的试验中，识别出生殖器的男性。并要求以三到四次访问的三周间隔返回，此时收集了血清，其生殖器菌菌株M. 被培养和表征。这些实验是前所未有的，因为最近的临床分离株（而不是实验室适应的菌株）将用于旅游研究。因此，我们提出1）表征MGPB序列在整个纵向研究中在不同时间点的演变，2）将MGPB中特定变量序列的清除与受感染男性中这些序列的发展与这些序列的发展相关，以及3）是否确定抗体是否确定这些变异序列与这些变体序列相吻合的群体介导的杀伤力增强。这项研究是在经济地使用一组极其有价值且良好的患者标本集以评估基因变异对这种新认识的这种病原体持续性的作用的创新性。这项研究很重要，因为它将部分揭示这种新认识的生殖器病原体中免疫逃避的机制。我们关注该细胞细菌的免疫病作用的潜在影响很大，因为可以鉴定出新的干预和治疗目标。