Candida albicans and Staphylococcus aureus dual species biofilms

描述（由申请人提供）：细菌种类金黄色葡萄球菌和人类真菌病原体白色念珠菌是血液和医院获得性感染的主要病原体。由这些不同的生物体引起的大多数感染与生物膜相关，因为它们能够粘附在各种表面上，导致持续和慢性感染。更重要的是，白色念珠菌和金黄色葡萄球菌经常在伤口、粘膜表面和宿主的各个部位共同分离。尽管它们的流行和它们在宿主中共存的临床推论，但在多微生物感染的背景下探索它们相互作用的影响的研究一直缺乏。基于体外和体内研究的广泛初步发现，本提案旨在验证这些生物在宿主中相互作用的假设，因为它们共存于粘膜表面，并对其致病潜力和感染过程产生重大影响。具体而言，本提案旨在利用这两个物种的临床菌株，证明白色念珠菌和金黄色葡萄球菌双物种生物膜的感染协同作用和侵袭性全身葡萄球菌感染。为此，我们建立了小鼠口腔黏膜共感染模型，以确定高侵袭性白色念珠菌菌丝穿透小鼠口腔黏膜是否会导致正常情况下无侵袭性但有逃避性的金黄色葡萄球菌的全身感染。此外，由于初步数据似乎暗示在动物模型的共感染过程中涉及双物种生物膜诱导的蛋白质表达，因此计划进行全球蛋白质表达分析，以描述特定毒力因子的表达。随后，鉴定的蛋白质对毒力增强的直接影响将通过基因敲除研究来阐明。综上所述，这些新的初步发现为进一步深入研究白色念珠菌和金黄色葡萄球菌之间复杂的相互作用提供了依据，因为这些常见病原体经常共同感染危重住院患者，导致显著的发病率和死亡率。我们期望实现这一提议的目标，作为一个范例，进一步真菌-细菌相互作用和多微生物疾病的领域。更重要的是，这些发现的传播将有助于设计新的治疗策略，旨在对抗真菌-细菌多微生物感染。

DESCRIPTION (provided by applicant): The bacterial species Staphylococcus aureus and the human fungal pathogen Candida albicans are among the leading pathogens in bloodstream and hospital-acquired infections. Most infections caused by these diverse organisms are biofilm-associated due to their ability to adhere to a variety of surfaces causing persistent and chronic infections. More importantly, C. albicans and S. aureus are often co-isolated from wounds, mucosal surfaces and various sites in the host. Despite their prevalence and the clinical inferences of their co-existence in a host, studies exploring the implications of their interaction within the context of polymicrobial infections have been lacking. Based on extensive preliminary findings from in vitro and in vivo studies, this proposal was formulated to validate the hypothesis that these organisms interact in the host as they co-exist on mucosal surfaces with significant impact on their pathogenic potential and the infectious process. Specifically, using clinical strains of both species, this proposal aims to demonstrate infectious synergism and invasive systemic staphylococcal infection due to C. albicans and S. aureus dual species biofilms. To that end, a murine model of oral mucosal co-infection was developed in order to determine whether the penetration of the mouse oral mucosa by the highly invasive C. albicans hyphae leads to systemic infection by the normally non-invasive yet evasive S. aureus. In addition, as preliminary data seem to implicate the involvement of dual-species biofilm-induced protein expression in the co-infectious process in the animal model, global protein expression analyses are planned in order to profile the expression of specific virulence factors. Subsequently, the direct effect of the identified proteins on virulence enhancement will be elucidated using gene knockout studies. Combined, these novel preliminary findings warrant further in depth investigations into the intricate interaction between C. albicans and S. aureus as these common pathogens frequently co-infect critically-ill hospitalized patients causing significant morbidity and mortality. We expect the fulfillment of the aims of this proposal to serve as a paradigm to further the field of fungal- bacterial interactions and polymicrobial diseases in general. More importantly, the dissemination of the findings generated will aid in the design of novel therapeutic strategies aimed at combating fungal-bacterial polymicrobial infections. PUBLIC HEALTH RELEVANCE: The bacterial species Staphylococcus aureus and the human fungal pathogen Candida albicans are capable of adhering on a variety of surfaces causing significant chronic biofilm-associated infections. These microbial species are also isolated together from various sites from infected patients. Yet despite their prevalence and pathogenesis, studies exploring the implications of their interaction within the context of polymicrobial or mixed infections have been lacking. To that end, using a mouse model of infection, we performed extensive preliminary studies which demonstrated enhanced virulence for these organisms when they co-exist in a host. In this application, we propose to perform additional in depth molecular and animal studies in order to confirm our preliminary findings and generate data to contribute to our understanding of the mechanisms leading to multi-microbial infections. We expect the findings generated from the accomplishment of this work to aid in the design of novel therapeutic strategies to combat polymicrobial infections.