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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要由细菌病原体鲍曼不动杆菌 (Ab) 引起的多重耐药 (MDR) 感染是以惊人的速度增长。如今，抗体临床分离株的 MDR 频率高于任何其他抗体革兰氏阴性细菌。为此，世界卫生组织将抗体列为治疗的重中之重。新抗菌疗法的研究和开发。 Ab 在很大程度上与医疗保健有关 - 获得性感染，即肺炎和败血症。然而，抗体引起尿路感染的能力感染（UTI），包括导管相关性尿路感染（CAUTI），未被充分认识。尽管有 20-30% 抗体分离物来自尿液来源，目前还没有建立模型来研究抗体尿路感染或抗体的分子基础尿路致病性抗体 (UPAb) 毒力。由于 UPAb 导致全球耐多药尿路感染的增加，因此有一个迫切需要创造新的 Ab UTI 疗法。因此，需要小鼠模型来研究 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 Ab 导管相关 UTI (CAUTI) 小鼠模型，用于检查小鼠植入物和膀胱定植，我们选择了 MDR 抗体分离株 AbCA1 作为模型菌株。 AbCA1 是从阿根廷一名女性尿路感染患者身上分离出来的。应变属于国际抗体克隆 ST25，这是一个系统发育上独特且非常重要的抗体谱系其病理生理学研究甚少的临床菌株。 AbCA1 携带一个大的 MDR 编码质粒， pAB5 属于 Ab 大接合质粒 (AbLCP) 家族，在多个、地理上多样化的抗体株。有趣的是，我们的初步研究结果表明 pAB5 可以改善在我们的 CAUTI 模型中存活，但在肺炎模型中毒力降低。坚持导管和尿路上皮构成了建立 CAUTI 的第一阶段。我们已经验证了我们的模型，显示删除在我们的 CAUTI 模型中，伴侣引座菌毛的缺失消除了 AbCA1 定植于导管和膀胱的能力。同样，删除糖蛋白酶 CpaA（T2SS 相关表达最丰富的酶之一）效应子，体外人尿液中 AbCA1 的生长减少以及 CAUTI 模型中的毒力。在这个应用，我们建议利用我们在抗体分子生物学和发病机制方面公认的专业知识来研究 Ab CAUTI 早期阶段涉及的细菌因素。我们将进一步调查因素参与粘附以及参与 UPAb 发病机制的细胞外和表面暴露元件。我们还将研究 pAB5 如何增强 AbCA1 的泌尿道致病状态。我们的工作表明 Ab 是不是一组具有停滞毒力因子的同质病原体；相反，菌株似乎获得独特的特征，使它们能够更好地在特定的宿主生态位中引起疾病。建立模型Ab 菌株和代表这些被忽视的感染的动物疾病模型对于阻止 UPAb 的努力至关重要以免加剧全球耐多药尿路感染负担。我们提出的模型和调查将服务于作为开发新型诊断和治疗方法的基础。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Replicative Acinetobacter baumannii strains interfere with phagosomal maturation by modulating the vacuolar pH.

复制型鲍曼不动杆菌菌株通过调节液泡 pH 值来干扰吞噬体成熟。

DOI：
发表时间：
2023-02-02
期刊：
影响因子：
0
作者：
Distel, Jesus S;Di Venanzio, Gisela;Mackel, Joseph J;Rosen, David A;Feldman, Mario F
通讯作者：
Feldman, Mario F

Evolutionarily stable gene clusters shed light on the common grounds of pathogenicity in the Acinetobacter calcoaceticus-baumannii complex.

进化稳定的基因簇揭示了醋酸钙不动杆菌-鲍曼不动杆菌复合体致病性的共同点。

DOI：
发表时间：
2022-06
期刊：
影响因子：
4.5
作者：
Djahanschiri, Bardya;Di Venanzio, Gisela;Distel, Jesus S;Breisch, Jennifer;Dieckmann, Marius Alfred;Goesmann, Alexander;Averhoff, Beate;Göttig, Stephan;Wilharm, Gottfried;Feldman, Mario F;Ebersberger, Ingo
通讯作者：
Ebersberger, Ingo

InvL, an Invasin-Like Adhesin, Is a Type II Secretion System Substrate Required for Acinetobacter baumannii Uropathogenesis.

InvL 是一种类似侵袭素的粘附素，是鲍曼不动杆菌尿路病理发生所需的 II 型分泌系统底物。

DOI：
发表时间：
2022-06-28
期刊：
影响因子：
6.4
作者：
Jackson;Di Venanzio, Gisela;Le, Nguyen;Scott, Nichollas E;Djahanschiri, Bardya;Distel, Jesus S;Pardue, Evan J;Ebersberger, Ingo;Feldman, Mario F
通讯作者：
Feldman, Mario F

The Glycoprotease CpaA Secreted by Medically Relevant Acinetobacter Species Targets Multiple O-Linked Host Glycoproteins.

医学相关不动杆菌菌种分泌的糖蛋白酶 CpaA 靶向多种 O 连接宿主糖蛋白。

DOI：
发表时间：
2020
期刊：
影响因子：
6.4
作者：
Haurat, M Florencia;Scott, Nichollas E;Di Venanzio, Gisela;Lopez, Juvenal;Pluvinage, Benjamin;Boraston, Alisdair B;Ferracane, Michael J;Feldman, Mario F
通讯作者：
Feldman, Mario F

Modern Acinetobacter baumannii clinical isolates replicate inside spacious vacuoles and egress from macrophages.

现代鲍曼不动杆菌临床分离株在宽敞的液泡内复制并从巨噬细胞排出。

DOI：
发表时间：
2021-08
期刊：
影响因子：
6.7
作者：
Sycz, Gabriela;Di Venanzio, Gisela;Distel, Jesus S;Sartorio, Mariana G;Le, Nguyen;Scott, Nichollas E;Beatty, Wandy L;Feldman, Mario F
通讯作者：
Feldman, Mario F