Molecular Insights into the Uropathogenesis of MDR Acinetobacter baumannii

耐多药鲍曼不动杆菌泌尿道发病机制的分子见解

• 批准号: 10549371
• 负责人: Mario Feldman
• 金额: $ 66.85万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-06 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549371
• 关键词: ATP binding cassette transporter 1; Acinetobacter; Acinetobacter Infections; Acinetobacter baumannii; Adherence; Adhesions; Animal Disease Models; Animals; Argentina; Bacteremia; Bacterial Adhesins; Biological Assay; Bladder; Categories; Catheters; Chromosomes; Clinical; Critical Illness; Data; Deposition; Development; Disease; Disease model; Elements; Family; Female; Fibrinogen; Foundations; Frequencies; Functional disorder; Future; Geography; Glycobiology; Glycoproteins; Gram-Negative Bacteria; Growth; Healthcare; Human; Immunocompromised Host; Implant; In Vitro; Infection; Inflammatory Response; International; Investigation; Ligands; Lung; Mediating; Modeling; Molecular; Molecular Biology; Molecular Chaperones; Multi-Drug Resistance; Multidrug-resistant Acinetobacter; Mus; Mutagenesis; Nosocomial pneumonia; Pathogenesis; Pathway interactions; Patients; Pattern; Performance; Phylogenetic Analysis; Pilum; Plasmids; Pneumonia; Predisposition; Protein Glycosylation; Proteins; Repression; Research Priority; Role; Septicemia; Source; Surface; System; Type II Secretion System Pathway; Urinary tract; Urinary tract infection; Urine; Urothelium; Virulence; Virulence Factors; Woman; Work; World Health Organization; antimicrobial; capsule; catheter associated UTI; community-acquired UTI; extracellular; host colonization; improved; in vivo; insight; mouse model; neglect; novel; novel diagnostics; novel therapeutics; pathogen; pathogenic bacteria; pneumonia model; protein expression; research and development; soft tissue; trait; urinary; ATP binding cassette transporter 1; Acinetobacter; Acinetobacter Infections; Acinetobacter baumannii; Adherence; Adhesions; Animal Disease Models; Animals; Argentina; Bacteremia; Bacterial Adhesins; Biological Assay; Bladder; Categories; Catheters; Chromosomes; Clinical; Critical Illness; Data; Deposition; Development; Disease; Disease model; Elements; Family; Female; Fibrinogen; Foundations; Frequencies; Functional disorder; Future; Geography; Glycobiology; Glycoproteins; Gram-Negative Bacteria; Growth; Healthcare; Human; Immunocompromised Host; Implant; In Vitro; Infection; Inflammatory Response; International; Investigation; Ligands; Lung; Mediating; Modeling; Molecular; Molecular Biology; Molecular Chaperones; Multi-Drug Resistance; Multidrug-resistant Acinetobacter; Mus; Mutagenesis; Nosocomial pneumonia; Pathogenesis; Pathway interactions; Patients; Pattern; Performance; Phylogenetic Analysis; Pilum; Plasmids; Pneumonia; Predisposition; Protein Glycosylation; Proteins; Repression; Research Priority; Role; Septicemia; Source; Surface; System; Type II Secretion System Pathway; Urinary tract; Urinary tract infection; Urine; Urothelium; Virulence; Virulence Factors; Woman; Work; World Health Organization; antimicrobial; capsule; catheter associated UTI; community-acquired UTI; extracellular; host colonization; improved; in vivo; insight; mouse model; neglect; novel; novel diagnostics; novel therapeutics; pathogen; pathogenic bacteria; pneumonia model; protein expression; research and development; soft tissue; trait; urinary

PROJECT SUMMARY/ABSTRACT Multidrug resistant (MDR) infections caused by the bacterial pathogen Acinetobacter baumannii (Ab) are increasing at alarming rates. Today the MDR frequencies among Ab clinical isolates are higher than any other Gram-negative bacterium. For this reason, the World Health Organization has categorized Ab as top priority for the research and development of new antimicrobial therapies. Ab is largely associated with healthcare- acquired infections, namely pneumonia and septicemia. However, the ability of Ab to cause urinary tract infections (UTI), including catheter-associated UTI (CAUTI), is underappreciated. Despite that 20-30% of the Ab isolates come from urinary sources, there is no established model to study Ab UTI or the molecular basis of uro-pathogenic Ab (UPAb) virulence. As UPAb are contributing to the rise of MDR UTI globally, there is a pressing need to create new Ab UTI therapies. Thus, there is demand for a murine model to study MDR-UPAb and to identify the bacterial factors critical for Ab UTI. We have developed the first Ab catheter-associated UTI (CAUTI) murine model to examine implant and bladder colonization in mice, and we have selected the MDR Ab isolate AbCA1 as model strain. AbCA1 was isolated from a female UTI patient in Argentina. The strain belongs to the international Ab clone ST25, a phylogenetically distinct and emergently important lineage of Ab clinical strains whose pathophysiology has been poorly studied. AbCA1 carries a large MDR-encoding plasmid, pAB5, which belongs to a family of Ab Large Conjugative Plasmids (AbLCPs) identified in multiple, geographically-diverse Ab strains. Interestingly, our preliminary findings show that pAB5 confers improved survival in our CAUTI model, but reduced virulence in a pneumonia model. Adherence to the catheter and urothelium constitutes the first stage in establishing CAUTI. We have validated our model showing that deletion of chaperone-usher pili abrogates AbCA1 ability to colonize the catheter and bladder in our CAUTI model. Similarly, deletion of the glycoprotease CpaA, one of the most abundantly expressed T2SS-associated effector, diminished AbCA1 growth in human urine in vitro and virulence in the CAUTI model. In this application, we propose to use our recognized expertise in Ab molecular biology and pathogenesis to investigate the bacterial factors involved in the early stages of Ab CAUTI. We will further investigate the factors involved in adherence and the extracellular and surface-exposed elements involved in UPAb pathogenesis. We will also investigate how pAB5 enhances the uro-pathogenic state of AbCA1. Our work reveals that Ab is not a homogenous group of pathogens with a stagnant battery of virulence factors; instead, strains appear to acquire unique traits that better equip them to cause disease in specific host niches. Establishing a model Ab strain and an animal disease model that represents these neglected infections is critical to efforts to stop UPAb from contributing to the growing global burden of MDR UTI. Our proposed models and investigations will serve as foundation for the development of novel diagnostics and therapeutics.

项目摘要/摘要 由细菌病原体鲍曼尼（AB）引起的多药耐药（MDR）感染是 以惊人的速度增加。如今，AB临床分离株中的MDR频率高于任何其他 革兰氏阴性细菌。因此，世界卫生组织已将AB归类为重中之重 新的抗菌疗法的研究和开发。 AB主要与医疗保健有关 获得感染，即肺炎和败血病。但是，AB引起尿路的能力 感染（UTI），包括导管相关的UTI（CAUTI），被低估了。尽管有20％至30％ AB分离株来自尿液来源，没有建立的模型来研究AB UTI或分子基础 URO-PANECONIC AB（UPAB）毒力。由于UPAB在全球MDR UTI的崛起中做出了贡献，因此有一个 紧迫需要创建新的AB UTI疗法。因此，需要一个鼠模型来研究mdr-upab 并确定对AB UTI至关重要的细菌因素。我们开发了第一个与AB导管相关的UTI （CAUTI）鼠模型检查小鼠中的植入物和膀胱定植，我们选择了MDR AB分离ABCA1作为模型应变。 ABCA1与阿根廷的女性UTI患者分离出来。应变 属于国际AB克隆ST25，这是AB的系统发育不同且新兴的谱系 病理生理学的临床菌株研究不足。 ABCA1带有大型MDR编码质粒， PAB5，属于AB家族大的共轭质粒（ABLCP） 地理多样性的AB菌株。有趣的是，我们的初步发现表明PAB5赋予了改善 在我们的cauti模型中的生存​​，但肺炎模型中的毒力降低。遵守导管和 尿铺上皮构成建立cauti的第一阶段。我们已经验证了模型，显示了删除 伴侣糖叠菌的菌毛消除了ABCA1在我们的cauti模型中定居于导管和膀胱的能力。 同样，糖蛋白酶CPAA的缺失，这是最丰富的T2SS相关的删除 效应子，在cauti模型中，人类尿液和毒力的ABCA1生长降低。在这个 应用，我们建议将我们在AB分子生物学和发病机理中使用公认的专业知识 研究AB CAUTI早期涉及的细菌因素。我们将进一步研究因素 参与依从性以及涉及UPAB发病机理的细胞外和表面暴露元素。 我们还将研究PAB5如何增强ABCA1的Uro致病状态。我们的工作表明AB是 不是一组同质的病原体，毒力因子停滞了；相反，菌株似乎 获得独特的特征，使他们能够在特定的宿主壁ches中引起疾病​​。建立模型AB 应变和代表这些被忽视感染的动物疾病模型对于阻止UPAB的努力至关重要 从增加MDR UTI的全球负担的贡献。我们提出的模型和调查将服务 作为开发新型诊断和治疗学的基础。