Candida albicans and Staphylococcus aureus dual species biofilms

白色念珠菌和金黄色葡萄球菌双物种生物膜

• 批准号: 8084204
• 负责人: MARY ANN Y JABRA-RIZK
• 金额: $ 36.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084204
• 关键词: Animal Model; Animals; Bacterial Adhesins; Binding; Blood Circulation; Candida albicans; Chronic; Clinical; Coculture Techniques; Complex; Confocal Microscopy; Critical Illness; Data; Development; Disease; Elements; Epithelial Cells; Epithelium; Global Change; Goals; Growth; Harvest; Human; Hyphae; In Vitro; Infection; Invaded; Investigation; Kidney; Lactate Dehydrogenase; Lead; Life; Mediating; Medical Microbiology; Microbial Biofilms; Microscopic; Microscopy; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Morphology; Mus; Nature; Nosocomial Infections; Oral; Oral mucous membrane structure; Organism; Pathogenesis; Patients; Penetration; Prevalence; Prevention; Principal Investigator; Process; Production; Property; Proteins; Proteomics; Research; Site; Staphylococcal Infections; Staphylococcus aureus; Surface; Systemic infection; Testing; Therapeutic; Tissues; Toxin; Transcription Repressor/Corepressor; Virulence; Virulence Factors; Work; Yeasts; base; clinically significant; combat; design; improved; in vivo; knockout gene; microbial; microbial colonization; mortality; mouse model; mutant; novel; novel strategies; novel therapeutics; pathogen; programs; protein expression; public health relevance; response; synergism

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.

描述（由申请人提供）：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都与生物膜相关，因为它们能够粘附在各种表面上，从而导致持续性和慢性感染。更重要的是，白色念珠菌和金黄色葡萄球菌通常从伤口、粘膜表面和宿主的各个部位共同分离。尽管它们很普遍并且临床推论它们在宿主中共存，但探索它们在多种微生物感染背景下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结果，制定该提案是为了验证以下假设：这些生物体在宿主粘膜表面共存时相互作用，对其致病潜力和感染过程产生重大影响。具体来说，利用这两个物种的临床菌株，该提案旨在证明白色念珠菌和金黄色葡萄球菌双物种生物膜引起的感染协同作用和侵袭性系统性葡萄球菌感染。为此，开发了口腔粘膜共同感染的小鼠模型，以确定高度侵袭性的白色念珠菌菌丝对小鼠口腔粘膜的渗透是否会导致通常非侵袭性但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动物模型中的共感染过程涉及双物种生物膜诱导的蛋白质表达，因此计划进行全局蛋白质表达分析，以分析特定毒力因子的表达。随后，将通过基因敲除研究阐明所鉴定的蛋白质对毒力增强的直接影响。综合起来，这些新颖的初步发现值得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，因为这些常见病原体经常共同感染危重住院患者，导致显着的发病率和死亡率。我们期望该提案目标的实现能够成为进一步发展真菌-细菌相互作用和多种微生物疾病领域的范例。更重要的是，所产生的研究结果的传播将有助于设计旨在对抗真菌-细菌多种微生物感染的新治疗策略。 公共卫生相关性：细菌种类金黄色葡萄球菌和人类真菌病原体白色念珠菌能够粘附在各种表面上，导致严重的慢性生物膜相关感染。这些微生物种类也是从受感染患者的不同部位一起分离出来的。然而，尽管它们的流行和发病机制，但仍缺乏探索它们在多种微生物或混合感染背景下相互作用的影响的研究。为此，我们使用小鼠感染模型进行了广泛的初步研究，结果表明，当这些微生物在宿主中共存时，它们的毒力会增强。在此应用中，我们建议进行额外的深入分子和动物研究，以证实我们的初步发现并生成数据，以有助于我们了解导致多种微生物感染的机制。我们期望这项工作的完成所产生的结果有助于设计对抗多种微生物感染的新治疗策略。