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

项目摘要 葡萄球菌和白色念珠菌是分离出的最常见的微生物组合 来自多种微生物的感染。白色念珠菌和金黄色葡萄球菌致病能力 这在很大程度上取决于它们形成生物膜并改变其转录组的能力 以不同的压力来确保在寄主中生存。转录水平的变化 网络还确保这些生物可以在组织中生长并在压力下生存 由先天免疫系统的细胞强加给它们。显著增强的 白色念珠菌和葡萄球菌混合生物膜对抗生素的体外耐受性 已经上报了。因此，除了形成增强和持久的 生物被膜、金黄色葡萄球菌和白色念珠菌的混合感染可能会影响基因表达，在 转而影响毒力和耐药性。因此，当务之急是 阐明这些病原体在多菌生物膜中的独特相互作用 在活体中，目标是提供对混合的动力学的总体洞察- 微生物种群是在人体内建立和调节的。为此，我们 开发了一种实用的和临床相关的皮下导管小鼠模型 描述金黄色葡萄球菌和白色念珠菌之间的分子相互作用 通过执行单一和混合的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，我们将用它们来阐明 体内生物被膜形成及耐药机制的研究 条件。我们的中心假设是，调控和转录途径 在体内培养的白色念珠菌和S。 金黄色葡萄球菌识别增强致病潜能的微生物表型 与生物膜相关的多菌感染的持久性和耐药性。

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.