Identifying niche specific adaptations in Acinetobacter baumannii

鉴定鲍曼不动杆菌的生态位特异性适应

• 批准号: 10449699
• 负责人: Mario Feldman
• 金额: $ 25.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-24 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449699
• 关键词: Acinetobacter; Acinetobacter baumannii; Acinetobacter baumannii pneumonia; Adhesions; Adopted; Alleles; Animal Model; Animals; Antibiotics; Attenuated; Bacteria; Bacterial Adhesins; Binding; Biology; Bladder; Blood; Catheters; Clinical; Communities; Critical Illness; Data; Deposition; Disease; Disease Outbreaks; Environment; Exhibits; Fibrinogen; Future; General Practitioners; Genetic Determinism; Genetic Markers; Genome; Growth; Indwelling Catheter; Infection; Link; Lung; Lung infections; Measures; Mediating; Microbial Biofilms; Modeling; Modernization; Molecular Chaperones; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mutagenesis; Operon; Organ; Osteomyelitis; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Phylogenetic Analysis; Pilum; Plasmids; Pneumonia; Polysaccharides; Predisposition; Proteins; Research; Respiratory System; Site; Source; Specific qualifier value; Specificity; Surface; System; Testing; Therapeutic Intervention; Tissues; Toxin; Triage; Urinary tract; Urine; Virulence; Virulence Factors; Virulent; base; carbapenem resistance; catheter associated UTI; clinically relevant; combat; comparative genomics; experimental study; genetic element; innovation; member; mortality; mouse model; novel; novel therapeutic intervention; opportunistic pathogen; pathogen; pathogenic bacteria; phenotypic biomarker; pneumonia model; receptor; research and development; respiratory; soft tissue; urinary

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.

抽象的 ACINETOBACTER BAUMANNII（AB），是临床上最相关的杆菌属的成员，是一种 机会性病原体。该细菌具有获得多药耐药性（MDR）的令人震惊的倾向， 与MDR-AB菌株相关的感染与更大的发病率和死亡率有关。因此， 抗碳青霉烯的AB最近在需要研究和开发的细菌的优先级清单中排名 新型治疗策略。尽管MDR-AB在全球范围内产生重大影响，但与其他 主要的MDR病原体，关于AB发病机理的了解相对较少。虽然AB最常见的原因 肺炎（40％的病例），在动物感染模型中没有使用肺部分离株研究AB肺炎。 AB通常还会感染其他细分市场，例如血液，尿路和软组织。经典，AB菌株 被认为是一组同质的机会病原体，在 至关重要的主人。结果，AB的研究工作经常在单个模型中推断出一个AB菌株的发现 感染以得出整个AB的结论。我实验室的最新数据挑战了这个概念 AB缺乏利基特异性。我们的回顾性分析表明，约有20％的AB临床分离株是 通常从尿液来源获得，通常是从留置导管的患者那里获得的。尽管有相关的统计数据， 在导管相关的尿路感染（CAUTI）的背景下，AB发病机理的研究是 不存在。因此，我的小组建立了AB Cauti的第一个鼠模型，并采用了它来表征 UPAB1，最近的MDR尿液分离物。使用该模型，我们收集了有遗传的证据 AB中影响利基特异性和感染结果的决定因素。在初步实验中， 我们已经感染了来自尿和呼吸源的AB菌株的小鼠，并确定了执行的菌株 在一个感染模型中很好，但在另一个感染模型中很差。我们假设这是基因确定的，特定于小众的 现代AB菌株发生了适应。在此提案中，我们将对特定于利基的AB菌株进行分类 或通才群体。使用比较基因组学，我们将确定遗传元素 负责特异性适应和毒力。我们希望识别出特异性的毒力 可能是创新抗生素独立疗法的新靶标的决定因素。此外，遗传 这项研究中确定的表型标记物可以帮助告知最佳分类实践和治疗性 打击潜在的AB暴发的干预措施。最后，我们期望确定现代的肝病和 研究界可以广泛采用的呼吸AB菌株，以更好地调查两个领先 AB疾病的表现。