Candida albicans biofilm dispersion as a key step during candidiasis

描述(申请人提供)：念珠菌病目前是美国和世界各地医院中第三常见的医院感染，白色念珠菌仍然是最常见的念珠菌病病原体。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，生物膜就有可能引发或延长感染，因为它提供了一个安全的避难所，微生物可以从那里入侵局部组织，播种新的感染部位，并抵制根除努力。生物膜的积累是附着、生长和分散过程平衡的结果。毫无疑问，在这些现象中，人们最不了解的是生物膜的分散。在白色念珠菌的情况下，这尤其令人担忧，因为生物被膜扩散是与易感患者的危及生命的临床感染相关的主要罪魁祸首：正是分离的细胞负责败血症，并在侵袭性疾病确立之前扩散到目标器官。重要的是，这两种临床表现(念珠菌血症和系统性侵袭性念珠菌病)都与较高的发病率和死亡率有关。因此，本研究的主要目的是考察生物膜的分散过程。为此，我们将：i)确定与白色念珠菌生物膜分散相关的环境信号；ii)确定生物膜分散的分子机制；iii)分析生物膜分散的酵母细胞的表型，特别是粘附性、耐药性和毒力。这项拟议的研究具有创新性，因为它研究了生物膜，这是现代微生物学的主要范式之一。此外，它还重点介绍了生物被膜分散的过程，这在过去基本上被白色念珠菌研究人员忽视了。与公共卫生的相关性：生物膜的形成对人类健康具有严重后果。这项研究背后的主要思想是，我们需要更好地了解白色念珠菌细胞是如何从生物膜中分离出来的，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，可能会大幅降低发病率、死亡率和延长住院时间，同时降低医疗成本。

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.