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

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.

项目总结/摘要 由细菌病原体鲍曼不动杆菌（Ab）引起的多药耐药（MDR）感染是 以惊人的速度增长。目前，临床分离株中的耐多药率高于其他任何临床分离株 革兰氏阴性菌。因此，世界卫生组织将Ab列为最优先考虑的疾病， 研究和开发新的抗微生物疗法。Ab主要与医疗保健相关- 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UTI（UTI），未得到充分重视。尽管如此，20-30%的 Ab分离株来自尿源，目前还没有建立模型来研究Ab UTI或其分子基础。 尿路致病性Ab（UPAb）毒力。由于UPAb在全球范围内导致MDR UTI的上升， 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Ab UTI的关键细菌因素。我们开发了第一个Ab导管相关UTI （CAUTI）小鼠模型来检查小鼠中的植入物和膀胱定植，我们选择了MDR Ab分离株AbCA 1作为模型菌株。AbCA 1分离自阿根廷的一名女性UTI患者。应变 属于国际Ab克隆ST 25，这是Ab的一个在遗传学上独特且紧急重要的谱系 病理生理学研究不充分的临床菌株。AbCA 1携带大的MDR编码质粒， pAB 5属于Ab大结合质粒（AbLCP）家族， 地理上多样化的Ab菌株。有趣的是，我们的初步研究结果表明，pAB 5赋予改善的 存活率在我们的ESTTI模型中，但在肺炎模型中毒性降低。对导管的粘附性， 尿道扩张术构成了建立尿道扩张术的第一阶段。我们已经验证了我们的模型，显示删除 分子伴侣引导皮利的存在消除了AbCA 1在我们的膀胱炎模型中定殖导管和膀胱的能力。 类似地，糖蛋白酶CpaA的缺失，其是最丰富表达的T2 SS相关蛋白酶之一。 在体外人尿中的AbCA 1生长和在ESTTI模型中的毒力减弱。在这 应用中，我们建议利用我们在Ab分子生物学和发病机制方面公认的专业知识， 探讨Ab ESTTI早期阶段涉及的细菌因素。我们将进一步调查这些因素 参与粘附和参与UPAb发病机制的细胞外和表面暴露元件。 我们还将研究pAB 5如何增强AbCA 1的尿路致病状态。我们的工作表明，Ab是 不是一组同质的病原体，具有一系列停滞的毒力因子;相反，菌株似乎 获得独特的特征，使它们更好地在特定的宿主生态位中引起疾病。建立模型Ab 代表这些被忽视的感染的菌株和动物疾病模型对于阻止UPAb的努力至关重要 导致耐多药尿路感染的全球负担日益加重。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的基础。

项目成果

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

• DOI: 10.1128/mbio.00258-22
• 发表时间: 2022-06-28
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Jackson-Litteken, Clay D.;Di Venanzio, Gisela;Nguyen-Hung Le;Scott, Nichollas E.;Djahanschiri, Bardya;Distel, Jesus S.;Pardue, Evan J.;Ebersberger, Ingo;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.

• DOI: 10.1371/journal.pgen.1010020
• 发表时间: 2022-06
• 期刊: PLoS genetics
• 影响因子: 4.5

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

• DOI: 10.1371/journal.ppat.1009802
• 发表时间: 2021-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Sycz G;Di Venanzio G;Distel JS;Sartorio MG;Le NH;Scott NE;Beatty WL;Feldman MF
• 通讯作者: Feldman MF

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

• DOI: 10.1128/mbio.02033-20
• 发表时间: 2020-10-06
• 期刊: mBio
• 影响因子: 6.4
• 作者: Haurat MF;Scott NE;Di Venanzio G;Lopez J;Pluvinage B;Boraston AB;Ferracane MJ;Feldman MF
• 通讯作者: Feldman MF