Mobile Genetic Elements and Clinical Outcomes in Staphylococcus aureus Bacteremia

项目摘要 抗菌素耐药性(AMR)及其对健康的影响已被公认为最严重的公共疾病之一 社会面临的健康威胁。值得注意的是，绝大多数获得性AMR基因是在移动设备上携带的 遗传元件(MGE)，包括质粒、插入序列和转座子。其中最 携带耐药基因的重要医院和社区相关病原菌是葡萄球菌 金黄色葡萄球菌，每年在美国造成80,000多人感染和11,000人死亡。S. 金黄色葡萄球菌很容易获得MGES，它涵盖了大多数菌株基因组的20%以上，这些 对苯唑西林等抗生素的耐药性的建立和广泛传播的核心因素 和万古霉素。此外，金黄色葡萄球菌能够引起广泛的感染，包括菌血症， 死亡率高达30%。利用从患者队列中收集的无与伦比的金黄色葡萄球菌菌株 在患有菌血症的中美洲和南美洲，我寻求建立一个框架，以确定和 利用细菌系统发育学、临床流行病学和机器对循环中的MGES进行比较 学习。这个数据集将作为我成为一名独立科学家的培训基础。要开始 在询问这个特殊的菌株集合时，我们已经产生了Illumina短读全基因组 1,087株金黄色葡萄球菌菌血症分离株的测序数据用于鉴定MGES，并将利用新型超长 阅读测序方法以充分描述这些元素的位置和变化。三位一体 这项建议的目的是阐明MGES在推动人类遗传多样性方面的作用 地方性金黄色葡萄球菌分支，并确定它们是否在受到选择性压力时作为适应热点 来自宿主免疫系统或抗生素。首先，我将在这个大范围内描述MGES的曲目 并应用基因顺序和贝叶斯时间测量的系统发育学来鉴定优势菌株 每个分支中的MGE以及它们被获取和丢失的频率。第二，我将评估MGE 从同一个体连续收集的菌株内的多样性。我假设这些MGE将是 主要变异点，将比单核苷酸多态(SNPs)更重要 适应抗生素等选择性压力。第三，我将确定临床(年龄、BMI和现在 合并症)和基因组特征(SNPs、MGES和基因)可以预测30天的死亡率 在我们的数据集中，金黄色葡萄球菌的主要分支。我推测这些基因和临床特征将是 对于每个支系都不同，因为他们拥有不同的MGE曲目。抗菌素耐药性中心 位于休斯顿的德克萨斯大学健康科学中心的微生物基因组学坚定地致力于 了解和减少AMR和AMR感染。这提供了一个特殊的环境来进行 我的研究阐明了MGES在金黄色葡萄球菌菌血症临床结局中的作用，并发展为 一名调查员，并参加培训，表示愿意向独立过渡。

Project Summary Antimicrobial resistance (AMR) and its impact on health has been recognized as one of the most serious public health threats facing society. Significantly, the vast majority of acquired AMR genes are carried on mobile genetic elements (MGEs), which include plasmids, insertion sequences, and transposons. One of the most important hospital and community-associated pathogens harboring resistance genes is Staphylococcus aureus, which causes more than 80,000 infections and 11,000 deaths each year in the United States. S. aureus readily acquire MGEs, which encompass more than 20% of the genome for most strains, and these elements have been central to the establishment and broad spread of resistance to antibiotics such as oxacillin and vancomycin. Additionally, S. aureus is capable of causing a wide range of infections, including bacteremia, with a mortality rate up to 30%. Utilizing an unparalleled collection of S. aureus strains from a cohort of patients in Central and South America with bacteremia, I seek to develop a framework for the identification and comparison of circulating MGEs through the use of bacterial phylogenetics, clinical epidemiology, and machine learning. This dataset will serve as the foundation for my training to become an independent scientist. To begin interrogating this exceptional strain collection, we have generated Illumina short-read whole genome sequencing data on 1,087 S. aureus bacteremia isolates to identify MGEs, and will leverage novel ultra-long read sequencing methodologies to fully characterize the position and variations of these elements. The three aims within this proposal are designed to elucidate the role of MGEs in driving the genetic diversification of endemic S. aureus clades, and identify if they serve as adaptation hotspots when put under selective pressure from the host immune system or antibiotics. First, I will characterize the repertoire of MGEs within this large cohort of isolates and apply gene-order and Bayesian time-measured phylogenetics to identify the predominant MGEs within each clade and how frequently they are acquired and lost. Second, I will assess the MGE diversity within isolates collected serially from the same individual. I hypothesize these MGEs will be the primary variation points and will be more important than single nucleotide polymorphisms (SNPs) to the adaptation to selective pressures such as antibiotics. Third, I will identify the clinical (age, BMI, and present comorbidities) and genomic (SNPs, MGEs, and genes) features that are predictive of the 30-day mortality in the predominant clades of S. aureus within our dataset. I theorize these genetic and clinical signatures will be different for each clade as they possess different repertoires of MGEs. The Center for Antimicrobial Resistance and Microbial Genomics in The University of Texas Health Sciences Center at Houston has a firm commitment to understanding and reducing AMR and AMR infections. This provides an exceptional environment to conduct my research elucidating the role of MGEs in the clinical outcomes of S. aureus bacteremia, and to develop as an investigator and participate in the training offered to make the transition to independence.