Genomic epidemiology of Neisseria gonorrhoeae with elevated MICs to cefixime

描述(由申请人提供)：本提案提出了一项为期五年的淋球菌生物学和流行病学研究职业发展计划。这位候选人正在接受传染病方面的培训。概述的提案将在美国提供全基因组序列分析和种群基因组学培训，为成为一名整合微生物序列分析和传染病流行病学的独立内科科学家做准备。这项工作将在哈佛大学公共卫生学院流行病学教授兼传染病动力学中心主任马克·利普西奇的指导下进行，并将与疾病控制和预防中心和惠康信托桑格研究所合作进行。 淋病的病原体淋病奈瑟氏菌对用于治疗淋病的每一种一线抗生素都产生了抗药性。随着头孢曲松(一种溴化能头孢菌素)耐药性的蔓延，已经没有廉价、单剂、耐受性好和有效的治疗方案了。在这项提案中，申请人旨在解决有关抗生素耐药淋球菌的出现和传播的基本问题，这里重点关注对头孢克辛(一种口服广谱头孢菌素)MIC升高的菌株。与疾病控制和预防中心淋球菌分离监测计划和惠康信托桑格研究所合作，拟议的工作使用大规模全基因组测序和流行病学相结合的基因组流行病学方法来探索来自美国各地的头孢克肟MIC升高的分离物是否是克隆的(特定目标1)，这种多样性如何与地理和人口特征匹配的头孢克肟敏感分离物的预期更大多样性(特定目标2)相比较，以及不同的地理区域和网络在多大程度上拥有分离的淋球菌谱系(特定目标3)。此外，利用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、混合感染的危险因素以及混合感染病例的血统多样性(具体目标4)。详细了解淋球菌中抗生素耐药性的出现、传播和潜在的基因多样性将有助于指导公共卫生干预和开发新的诊断和治疗策略。 相关性：美国每年确诊的淋病病例超过30万例，使其成为报告第二多的传染病。虽然自抗生素时代开始以来，治疗一直是直截了当的，但淋病的病原体淋球菌已经对所有用于治疗它的一线抗生素产生了顺序耐药性，包括现在对广谱头孢菌素的耐药性。这项研究项目的主要目标是更多地了解抗生素耐药性是如何在人群和淋病奈瑟菌生物学中出现和传播的，从而为指导公共卫生干预、诊断方法和治疗方案提供见解。

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.