C. albicans and S. aureus Catheter Infections: Clinical Implications and Therapy

白色念珠菌和金黄色葡萄球菌导管感染：临床意义和治疗

基本信息

批准号：
9289824
负责人：
MARY ANN Y JABRA-RIZK
金额：
$ 38.73万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-21 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9289824
关键词：
Adhesions Adult Animal Model Antimicrobial Resistance Atomic Force Microscopy Bacteremia Binding Candida albicans Catheters Cells Child Clinical Complex Data Disease Drug resistance Ensure Evaluation Gene Expression Generations Genes Genetic Transcription Genus staphylococcus Goals Human Human body Imaging Device Implant In Vitro Infection Innate Immune System Investigation Lead Medical Device Microbial Biofilms Microscopy Molecular Monitor Morbidity - disease rate Organism Outcome Pathogenicity Pathway interactions Patients Phenotype Population Reporting Resistance development Risk Factors Signal Transduction Spectrum Analysis Staphylococcus aureus Stress Surface System Testing Tissues Treatment Failure Validation Virulence Work antimicrobial bioluminescence imaging candidemia clinically relevant co-infection comparative design differential expression drug development imaging system implantable device in vitro Model in vivo insight intravital imaging intravital microscopy microbial microorganism microorganism interaction mortality mouse model mutant new therapeutic target pathogen response subcutaneous tool transcriptome transcriptome sequencing transcriptomics treatment strategy

项目摘要

Project Summary Staphylococci and C. albicans are the most frequent combination of organisms isolated from polymicrobial infections. The ability of C. albicans and S. aureus to cause disease largely depends on their ability to form biofilms and alter their transcriptome in response to different stresses to ensure survival in the host. Changes in the transcriptional network also ensure that these organisms can grow in tissues and survive stresses inflicted upon them by cells of the innate immune system. Significantly, enhanced in vitro tolerance to antimicrobials in C. albicans and staphylococci mixed biofilms has been reported. Consequently, in addition to formation of enhanced and persistent biofilms, co-infection with S. aureus and C. albicans may influence gene expression, in turn impacting virulence and drug resistance. Therefore, it has become imperative to elucidate the unique interactions between these pathogens within polymicrobial biofilms in vivo with the goal of providing overall insights into the dynamics of how mixed- microbial populations are established and regulated in the human body. To that end, we developed a practical and clinically-relevant subcutaneous catheter mouse model to characterize the molecular interplay between S. aureus and C. albicans as they co- infect a host by performing comparative transcriptomics analysis of single and mixed- species biofilms. Further, we designed feasible non-invasive bioluminescence imaging and intravital microscopy systems as tools, which we will use to elucidate the mechanisms of biofilm formation and development of drug resistance under in vivo conditions. Our central hypothesis is that the regulatory and transcriptional pathways uniquely expressed during in vivo-grown polymicrobial biofilms of C. albicans and S. aureus identify microbial phenotypes of enhanced pathogenic potential central to the persistence and antimicrobial resistance of biofilm-associated polymicrobial infections.

项目概要葡萄球菌和白色念珠菌是最常见的分离微生物组合来自多种微生物感染。白色念珠菌和金黄色葡萄球菌致病的能力很大程度上取决于它们形成生物膜和改变转录组的能力不同的压力以确保在宿主中的生存。转录的变化网络还确保这些生物体可以在组织中生长并在压力下生存先天免疫系统的细胞对它们造成的。显着增强的是白色念珠菌和葡萄球菌混合生物膜对抗菌药物的体外耐受性被举报。因此，除了形成增强和持久的生物膜、金黄色葡萄球菌和白色念珠菌的共同感染可能会影响基因表达，进而影响毒力和耐药性。因此，当务之急是阐明多微生物生物膜内这些病原体之间的独特相互作用体内，目标是提供对如何混合的动态的整体见解微生物种群在人体内建立并受到调节。为此，我们开发了一种实用且临床相关的皮下导管小鼠模型表征金黄色葡萄球菌和白色念珠菌之间的分子相互作用，因为它们共同通过对单一和混合的病毒进行比较转录组学分析来感染宿主物种生物膜。此外，我们设计了可行的非侵入性生物发光成像和活体显微镜系统作为工具，我们将用它来阐明体内生物膜形成和耐药性发展机制状况。我们的中心假设是调节和转录途径在白色念珠菌和白色念珠菌体内生长的多种微生物生物膜中独特表达。金黄色葡萄球菌识别具有增强致病潜力的微生物表型生物膜相关的多种微生物感染的持续性和耐药性。