Identifying niche specific adaptations in Acinetobacter baumannii

摘要 鲍曼不动杆菌（Ab）是不动杆菌属中临床上最相关的成员，是一种耐药菌。 机会致病菌这种细菌具有获得多药耐药性（MDR）的惊人倾向， 与MDR-Ab菌株相关的感染与更高的发病率和死亡率有关。因此，委员会认为， 耐碳青霉烯类抗体最近在世界卫生组织需要研究和开发的细菌优先名单上名列前茅 新的治疗策略。尽管MDR-Ab在全球范围内产生了重大影响，但与其他药物相比， 主要的MDR病原体，相对知之甚少的Ab发病机制。虽然Ab最常引起 肺炎（40%的病例），没有肺分离物用于在动物感染模型中研究Ab肺炎。 抗体也通常感染其他壁龛，如血液，泌尿道和软组织。传统上，Ab菌株 被认为是一组同质的机会致病菌， 重症患者因此，Ab研究工作通常从单一模型中的一种Ab菌株推断结果 来得出关于Ab整体的结论。我的实验室最近的数据对这个概念提出了挑战 抗体缺乏生态位特异性我们的回顾性分析表明，约20%的Ab临床分离株是 从尿液来源获得，通常来自留置导管的患者。尽管有这些相关的统计数据， 在导管相关性尿路感染（CANTI）背景下， 根本不存在因此，我的小组建立了第一个小鼠模型的抗体，并利用它来表征 UPAB 1，一种最近的MDR尿液分离株。利用这个模型，我们收集到的证据表明， 抗体中的决定因素影响生态位特异性和感染结果。在初步实验中， 我们用来自泌尿和呼吸道的Ab菌株感染小鼠， 在一个感染模型中表现良好，但在另一个模型中表现不佳。我们假设基因决定的，特定的生态位 在现代Ab菌株中发生了适应。在本提案中，我们将按生态位特异性对Ab菌株进行分类。 或者是多面手团体。利用比较基因组学，我们将确定遗传因素 负责生态位特异性适应和毒性。我们希望能鉴定出特定生态位的毒力 这些决定因素可能是创新的非药物依赖性疗法的新靶点。此外，基因 在这项研究中发现的表型标记物可以帮助告知最佳的分诊实践和治疗 采取干预措施，防止潜在的抗体爆发。最后，我们希望能够确定现代尿路疾病和 呼吸道抗体菌株，可以广泛采用的研究界，以更好地调查两个主要的 Ab疾病的表现。

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.