Candida albicans biofilm dispersion as a key step during candidiasis

描述（由申请人提供）：念珠菌病现在是美国和世界范围内医院第三大常见的医院感染，白色念珠菌仍然是念珠菌病最常见的病原体。不幸的是，这些感染的死亡率高得令人无法接受。念珠菌病通常与生物膜的形成有关，一旦形成，生物膜就有可能通过提供一个安全的避难所来启动或延长感染，生物体可以从该避难所侵入局部组织，播种新的感染位点并抵抗根除努力。生物膜的积累源于附着、生长和分散过程的平衡。毫无疑问，在这些现象中，最不为人所知的是生物膜的分散。对于白色念珠菌，这尤其令人担忧，因为在易感患者中，生物膜分散是与危及生命的临床感染相关的主要罪魁祸首：正是分离的细胞导致败血症，并在侵袭性疾病建立之前传播到目标器官。重要的是，这两种临床表现（念珠菌病和全身侵袭性念珠菌病）都与高发病率和高死亡率有关。因此，本研究的主要目的是研究生物膜的分散过程。为此，我们将：1)确定与白色念珠菌生物膜分散相关的环境信号；2)确定生物膜分散的分子机制；3)分析从生物膜分散的酵母细胞的表型，特别强调粘附特性、耐药性和毒力。生物膜是现代微生物学研究的主要范式之一，具有创新意义。此外，它侧重于一个过程，生物膜分散，这在很大程度上被过去的白色念珠菌研究人员所忽视。公共卫生相关性：生物膜的形成对人类健康有严重后果。这项研究背后的主要想法是，我们需要更好地了解白色念珠菌细胞如何从生物膜中分离或分离，因为这些细胞负责随后在不同器官中建立感染。如果我们阻止这一关键步骤，它可能会导致发病率、死亡率和住院时间的大幅减少，同时降低医疗保健费用。

DESCRIPTION (provided by applicant): Candidiasis now represents the third most frequent nosocomial infection in hospitals both in the US and worldwide, and C. albicans remains the most frequent causative agent of candidiasis. Unfortunately these infections carry unacceptably high mortality rates. Candidiasis is often associated with biofilm formation and once established, biofilms have the potential to initiate or prolong infections by providing a safe sanctuary from which organisms can invade local tissue, seed new infection sites and resist eradication efforts. Biofilm accumulation results from the balance of attachment, growth, and dispersion processes. Without any question, of these phenomena, the least understood is biofilm dispersion. In the case of C. albicans this is particularly worrisome because biofilm dispersion is the step that represents the main culprit associated with life-threatening clinical infections in susceptible patients: it is precisely the detached cells that are responsible for septicemia and for dissemination to target organs prior to the establishment of invasive disease. Importantly, both of these clinical manifestations (candidemia and systemic invasive candidiasis) are associated with the high morbidity and mortality rates. Therefore, the main objective of the proposed studies is to examine the process of biofilm dispersion. To this end we will: i) identify the environmental signals associated with C. albicans biofilm dispersion, ii) identify the molecular mechanisms involved in biofilm dispersion and iii) analyze the phenotypes of yeast cells dispersed from the biofilm, with special emphasis on adhesive properties, drug resistance and virulence. The proposed research is innovative since it studies biofilms, one of the major paradigms of modern microbiology. Moreover, it focuses on a process, biofilm dispersion, that has largely been ignored in the past by C. albicans investigators. PUBLIC HEALTH RELEVANCE: Biofilm formation has severe consequences for human health. The main idea behind this study is that we need to better understand how C. albicans cells detach or separate from biofilms, since these cells are responsible for the subsequent establishment of infections in different organs. If we prevent this critical step, it may lead to a substantial reduction in morbidity, mortality and extended hospital stay, while simultaneously reducing healthcare costs.