Genomic epidemiology of Neisseria gonorrhoeae with elevated MICs to cefixime

描述（由申请人提供）：该提案提出了一个为期五年的研究职业发展计划，在淋病奈瑟菌生物学和流行病学的研究。该候选人正在接受传染病培训。该计划将在美国提供全基因组序列分析和群体基因组学方面的培训，为将来成为一名整合微生物序列分析和传染病流行病学的独立医生兼科学家做准备。这项工作将在哈佛公共卫生学院流行病学教授兼传染病动力学中心主任Marc Lipsitch的指导下进行，并将与疾病控制和预防中心和威康信托桑格研究所合作进行。 N.淋病是淋病的病原体，已经对用于治疗淋病的每一种一线抗生素产生了抗生素耐药性。随着对头孢曲松（一种广谱头孢菌素）的耐药性的传播，没有便宜、单剂量、耐受性好和有效的治疗方案。在本提案中，申请人旨在解决有关抗生素耐药淋球菌出现和传播的基本问题，此处重点关注对头孢克肟（一种口服广谱头孢菌素）MIC升高的分离株。与疾病控制和预防中心淋球菌分离株监测计划和威康信托桑格研究所合作，拟议的工作使用基因组流行病学方法，结合大规模全基因组测序和流行病学，以探索来自美国各地的对头孢克肟MIC升高的分离株是否是克隆的（具体目标1），这种多样性如何与地理和人口统计学特征匹配的头孢克肟敏感分离株的预期更大多样性进行比较（具体目标2），以及不同地理区域和网络在多大程度上存在分离的淋球菌谱系（具体目标3）。此外，使用来自马萨诸塞州公共卫生部的一组样本，拟议的工作将调查混合淋球菌感染的程度、混合感染的风险因素以及混合感染病例中谱系的多样性（具体目标4）。详细了解淋球菌抗生素耐药性的出现、传播和潜在的基因型多样性将有助于指导公共卫生干预措施以及新型诊断和治疗策略的开发。 相关性：美国每年诊断出超过30万例淋病，使其成为第二大报告的传染病。虽然自抗生素时代开始以来，治疗一直很简单，但淋病的病原体淋病奈瑟菌已对用于治疗它的所有一线抗生素产生耐药性，包括现在对广谱头孢菌素的耐药性。该研究项目的主要目标是了解更多关于抗生素耐药性如何出现并通过N.淋病，从而提供见解，以帮助指导公共卫生干预措施，诊断方法和治疗方案。

DESCRIPTION (provided by applicant): This proposal presents a five-year research career development program in the study of Neisseria gonorrhoeae biology and epidemiology. The candidate is training in Infectious Diseases. The outlined proposal will provide training in the us of whole-genome sequence analysis and population genomics in preparation for a career as an independent physician-scientist integrating microbial sequence analysis and epidemiology of infectious diseases. The work will be conducted under the mentorship of Marc Lipsitch, Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health, and will be pursued in collaboration with the Center for Disease Control and Prevention and the Wellcome Trust Sanger Institute. N. gonorrhoeae, the causative agent of gonorrhea, has developed antibiotic resistance to each of the first line antibiotics used to treat it. With the spread of resistance to ceftriaxone, a brod-spectrum cephalosporin, no treatment regimen remains that is cheap, single dose, well tolerated, and effective. In this proposal, the applicant aims to address fundamental questions about the emergence and spread of antibiotic resistant gonococcus, here focusing on isolates with elevated MICs to cefixime, an oral broad-spectrum cephalosporin. In collaboration with the Center for Disease Control and Prevention Gonococcal Isolate Surveillance Program and the Wellcome Trust Sanger Institute, the proposed work uses genomic epidemiological approaches combining large-scale whole-genome sequencing and epidemiology to explore whether isolates with elevated MICs to cefixime from across the United States are clonal (specific aim 1), how this diversity compares to the expected greater diversity in cefixime susceptible isolates matched by geography and demographic characteristics (specific aim 2), and to what extent differing geographic regions and networks harbor segregated gonococcal lineages (specific aim 3). Further, using a set of samples from the Massachusetts Department of Public Health, the proposed work will investigate the extent of mixed gonococcal infections, the risk factors for mixed infection, and the diversity of lineages in cases of mixed infection (specific aim 4). Detailed understanding of the emergence, spread, and underlying genotypic diversity of antibiotic resistance in gonococcus will help guide public health interventions and development of novel diagnostic and therapeutic strategies. RELEVANCE: Over 300,000 cases of gonorrhea are diagnosed annually in the United States, making it the second most reported of infectious diseases. While since the start of the antibiotic era treatment has been straightforward, Neisseria gonorrhoeae, the causative agent of gonorrhea, has become sequentially resistant to all the first line antibiotics that have been used to treat it, including now resistance to broad-spectrum cephalosporins. The main goal of this research project is to understand more about how antibiotic resistance emerges and spreads through the population and the biology of N. gonorrhoeae, thereby providing insights to help guide public health interventions, diagnostic approaches, and treatment regimens.