Genomics of S. Aureus Colonization after Initial and Recurrent Skin Infections and the Impact of Antibiotics

项目摘要 金黄色葡萄球菌是一种可以无害地在人体上生存的细菌（即，殖民化），但它是 也是皮肤和软组织感染（SSTI）、血流感染和 肺炎耐甲氧西林表皮葡萄金黄色葡萄球菌（MRSA）菌株对几乎所有与 青霉素尤其令人担忧，在美国每年有超过11，000人死亡。 50%的初始MRSA SSTI患者在12个月内复发。将是有益 了解哪些患者复发风险高，以便以最佳方式治疗， 复发性感染然而，现在我们不知道谁是复发的高风险。USA 300 MRSA菌株 是美国MRSA感染的最常见原因，尤其是SSTI。使用整体的新方法 基因组测序（WGS）可用于跟踪MRSA随着时间的推移而发生的进化变化， 人体的人们对MRSA随着时间的推移而发展的社区知之甚少，他们有多多样， 当一个人服用抗生素时，它们是如何受到影响的，以及MRSA的遗传变化与之相关 伴随复发性感染或长期定植的发作。我们建议对7,000例MRSA进行WGS研究 从400名MRSA SSTI患者中获得的分离株，收集时间超过一年。我们将测试400 在3个身体部位进行的拟议研究中，受试者每季度进行一次，为期一年，以解决这些未知因素， 时间，确定哪些细菌基因随着USA 300和其他MRSA菌株类型的生长而随时间变化， 在身体上进化。殖民细菌不断与人类宿主和环境相互作用。 因此，我们将评估这些基因的变化，在殖民细菌随着时间的推移，以及人口， 行为、抗生素暴露和医学特征，以确定其 对复发性感染风险的相对影响。我们的中心假设是，USA 300和密切相关的 (CC8)菌株，独立于宿主特征：1）在皮肤上定殖较长时间，并引起 复发性感染; 2）更可能导致需要医疗干预的感染; 3）更可能 在抗生素治疗后比其他菌株类型作为殖民者存活。我们还假设， 定植MRSA的多样性是长期定植和生存挑战能力的预测因子 抗生素。我们的假设将使用基因组数据分析和 计算机模拟我们还将测试我们收集的MRSA分离株，以确定是否有特定的遗传 变化导致MRSA适应性的变化，如通过其生长速率的变化所测量的，相对于 早期培养的菌株来自同一受试者。我们的目标是确定哪些临床治疗导致最 存活的S.金黄色葡萄球菌群体，以及这是否与低 复发感染的可能性。我们将应用拟议研究的发现来识别MRSA患者 这些人有很高的复发感染风险，以便为他们提供最好的预防治疗。

Project Summary Staphylococcus aureus is a bacterium that can live on the human body harmlessly (i.e., colonization), but it is also among the most common causes of skin and soft tissue infections (SSTIs), bloodstream infections, and pneumonia. Methicillin-resistant S. aureus (MRSA) strains that are resistant to nearly all antibiotics related to penicillin are particularly concerning, killing more than 11,000 people each year in the U.S. Furthermore, up to 50% of patients with an initial MRSA SSTI suffer from a recurrent SSTI within 12 months. It would be useful to know which patients are at high risk of recurrence so that they could be treated in the best way to prevent the recurrent infection. However, now we do not know who is at high risk of recurrence. The USA300 MRSA strain is the most common cause of MRSA infections in the U.S., especially SSTIs. New methods using whole genome sequencing (WGS) are available to track the evolutionary change in MRSA over time as it grows on the human body. Little is known about the communities of MRSA that develop over time, how diverse they are, how they are affected when a person takes an antibiotic, and what genetic changes in MRSA are associated with the onset of a recurrent infection or prolonged colonization. We propose a WGS study of 7,000 MRSA isolates obtained from 400 people with a MRSA SSTI collected over a one-year period. We will test the 400 subjects in the proposed study at 3 body sites quarterly over a year to address these unknowns for the first time, determining which bacterial genes change over time as USA300 and other MRSA strain types grow and evolve on the body. Colonizing bacteria are constantly interacting with their human hosts and the environment. We will therefore assess these gene changes in the colonizing bacteria over time as well as the demographic, behavioral, antibiotic exposure, and medical characteristics of studied human subjects to determine their relative impacts on the risk of a recurrent infection. Our central hypothesis is that USA300 and closely related (CC8) strains, independent of host characteristics: 1) colonize the skin for a longer period of time and cause recurrent infections; 2) more likely cause infections that require medical intervention; and 3) are more likely to survive as colonizers after antibiotic treatment than other strain types. We also hypothesize that a higher level of diversity among colonizing MRSA is a predictor of long-term colonization and ability to survive challenge with antibiotics. Our hypotheses will be assessed using a combination of analysis of genome data and computer modeling. We will also test the MRSA isolates that we collect to determine if specific genetic changes lead to changes in the fitness of MRSA, as measured by changes in their growth rate, relative to strains cultured earlier from the same subject. We aim to identify which clinical treatments lead to the most dramatic reduction in fitness of the surviving S. aureus population, and whether this is associated with lower likelihood of recurrent infections. We will apply the discoveries of the proposed study to identify MRSA patients at high risk of recurrent infections in order to give them the best preventive treatment.