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

项目摘要 葡萄球菌和C.白色念珠菌是最常见的微生物分离组合 多种微生物感染C. albicans和S.金黄色葡萄球菌致病 这在很大程度上取决于它们形成生物膜并相应改变其转录组的能力 以确保在宿主体内存活转录水平的变化 网络还确保这些生物体能够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伤害。显著增强， C.对抗生素的体外耐受性白色念珠菌和葡萄球菌混合生物膜 被举报。因此，除了形成增强的和持久的 生物膜、与S. aureus和C.白色念珠菌可能影响基因表达， 反过来影响毒力和耐药性。因此，当务之急是 阐明这些病原体在多微生物生物膜内的独特相互作用 在体内的目标是提供全面的见解，如何混合的动态- 微生物种群在人体内建立和调节。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， 描述了S. aureus和C.白色念珠菌，因为他们共同- 通过对单个和混合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 生物膜形成机制和体内耐药性的发展 条件我们的中心假设是，调控和转录途径 在体内生长的C. albicans和S. 金黄色葡萄球菌鉴定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久性和抗菌素耐药性。

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.