Identifying niche specific adaptations in Acinetobacter baumannii

摘要 鲍曼不动杆菌(Ab.)是临床上最具临床相关性的不动杆菌属成员。 机会主义病原体。这种细菌具有获得多药耐药性(MDR)的惊人倾向， 与多药耐药抗体株相关的感染与更高的发病率和死亡率有关。因此， 耐碳青霉烯单胞菌最近位居世卫组织需要研究和开发的细菌优先名单之首 新的治疗策略。尽管MDR-Ab在全球范围内产生了重大影响，但与其他 主要的MDR病原体，对抗体的发病机制知之甚少。尽管抗体最常见的原因是 肺炎(40%)，目前尚无肺分离株用于动物感染模型中抗体肺炎的研究。 AB还通常感染其他利基环境，如血液、尿路和软组织。经典的是，抗体菌株 被认为是一组同质的机会病原体，表现出不分青红皂白的毒性 病危的东道主。因此，抗体研究工作通常从单一模型中的一种抗体菌株推断结果 得出关于抗体作为一个整体的结论。我实验室最近的数据对这一概念提出了挑战 该抗体缺乏生态位特异性。我们的回顾分析表明，约20%的抗体临床分离株是 来自尿液来源，通常来自留置导尿管的患者。尽管有这个相关的统计数据， 导管相关性尿路感染(CAUTI)中抗体发病机制的研究 根本不存在。因此，我的团队建立了第一个AbCAUTI小鼠模型，并利用它来表征 UPAB1，一种最新的耐多药尿路分离物。利用这一模型，我们收集到的证据表明， 抗体中影响生态位特异性和感染结局的决定因素。在初步实验中， 我们用来自尿路和呼吸道的抗体菌株感染小鼠，并鉴定出具有 在一种感染模型中表现良好，但在另一种感染模式中表现不佳。我们假设，基因决定的，特定于生态位的 在现代抗体株中已经发生了适应。在这项建议中，我们将把抗体菌株分类为特定的生态位 或多面手团体。利用比较基因组学，我们将确定遗传因素 负责特定生态环境的适应和毒力。我们希望确定特定于小众的毒力 可能成为创新的抗生素非依赖性疗法的新靶点的决定因素。此外，基因 这项研究中确定的表型标记物可以帮助提供最佳分类实践和治疗信息 抗击潜在抗体暴发的干预措施。最后，我们希望鉴定现代致病和尿路疾病 可被研究界广泛采用的呼吸道抗体菌株，以更好地研究两个领先的 抗体病的临床表现。

Abstract Acinetobacter baumannii (Ab), the most clinically relevant member of the Acinetobacter genus, is an opportunistic pathogen. This bacterium has an alarming predisposition to acquire multi-drug resistance (MDR), and infections associated with MDR-Ab strains are linked to greater morbidity and mortality. Accordingly, carbapenem-resistant Ab recently topped the WHO priority list of bacteria that require research and development of novel therapeutic strategies. Despite the significant worldwide impact of MDR-Ab, when compared to other major MDR pathogens, relatively little is known about Ab pathogenesis. Although Ab most commonly causes pneumonia (40 % of cases), no lung isolates have been used to study Ab pneumonia in animal infection models. Ab also commonly infects other niches such as blood, the urinary tract, and soft-tissues. Classically, Ab strains are regarded as a homogenous group of opportunistic pathogens displaying niche-indiscriminate virulence in critically-ill hosts. As a result, Ab research efforts often extrapolate findings from one Ab strain in a single model of infection to draw conclusions about Ab as a whole. Recent data from my lab has challenged the concept that Ab lacks niche-specificity. Our retrospective analysis indicated that ~20% of Ab clinical isolates are obtained from urinary sources, often from patients with indwelling catheters. Despite this relevant statistic, research on Ab pathogenesis in the context of catheter-associated urinary tract infection (CAUTI) was nonexistent. Thus, my group established the first murine model of Ab CAUTI and employed it to characterize UPAB1, a recent MDR urinary isolate. Employing this model, we have collected evidence that there are genetic determinants in Ab that influence both niche specificity and the infection outcome. In preliminary experiments, we have infected mice with Ab strains from urinary and respiratory sources and identified strains that perform well in one infection model, but poorly in the other. We hypothesize that genetically determined, niche-specific adaptations have occurred in modern Ab strains. In this proposal we will classify Ab strains in niche-specific or generalist groups. Employing comparative genomics, we will determine the genetic elements responsible for niche-specific adaptations and virulence. We expect to identify niche-specific virulence determinants that may be novel targets for innovative antibiotic-independent therapies. Furthermore, the genetic and phenotypic markers identified in this study could help inform the best triage practices and therapeutic interventions to combat potential Ab outbreaks. Finally, we expect to identify modern uropathogenic and respiratory Ab strains that can be broadly adopted by the research community to better investigate two leading manifestations of Ab disease.