Role of phosphatidylethanolamine in regulating virulence in Candida albicans

描述（由申请人提供）：念珠菌属是人类最重要的真菌病原体，特别是白色念珠菌，是口咽念珠菌病的最常见原因，口咽念珠菌病是一种感染，影响患有获得性免疫缺陷综合征（AIDS）的患者以及其他疾病。念珠菌也是重症监护病房全身感染的第四大常见原因（约30%死亡率）。该奖学金提案探讨了磷脂磷脂酰乙醇胺（PE）和磷脂酰丝氨酸（PS）通过影响信号转导途径影响毒力的假设，这些信号转导途径调节粘附和侵入宿主组织所必需的毒力因子，以及逃避宿主的免疫反应。关于磷脂合成途径如何调节疾病知之甚少，但其中一些途径与哺乳动物不同，可能提供新的药物靶点。在C.白色念珠菌。从头途径从PS合成PE，PS本身仅由一种酶Cho 1 p合成。此外，肯尼迪途径从细胞外乙醇胺制造PE。完全阻断PS和/或PE从头合成的突变体（分别为cho 1///）是无毒的，PE显著下降，使细胞壁葡聚糖（真菌感染的免疫标记物）暴露于免疫系统的增强检测中，并且粘附侵入宿主上皮细胞的能力较差。此外，这些突变体是乙醇胺营养缺陷型， 突变体在宿主中由于乙醇胺供应不足而遭受适应性缺陷。假设完全阻断从头PE合成途径的突变通过损害细胞内的细胞信号传导级联来影响毒力，导致参与宿主粘附和免疫逃避的细胞表面蛋白的呈递发生急剧变化。PE合成的这些变化也可能降低C.白念珠菌在宿主中由于乙醇胺营养缺陷型。这一假设将在三个目标进行测试：1）观察已知参与毒力调节和粘附宿主组织的细胞信号传导途径的差异（即。Rim 101途径），2）确定PS和PE是否在逃避免疫应答中起作用3）发现乙醇胺（PE的已知底物）的营养缺陷型是否影响突变体在宿主中的毒力。

DESCRIPTION (provided by applicant): Candida species are the most important fungal pathogens of humans, and Candida albicans, in particular, is the most common cause of oropharyngeal candidiasis, which is an infection that affects patients suffering from Acquired Immune Deficiency Syndrome (AIDS) among other ailments. Candida are also the fourth most common cause of systemic infections (~30% mortality rate) in intensive care units This fellowship proposal explores the hypothesis that the phospholipids phosphatidylethanolamine (PE) and phosphatidylserine (PS) affect virulence by affecting signal transduction pathways that regulate virulence factors necessary for adhering to and invading host tissues, as well as evasion of the host's immune response. Little is known about the how phospholipid synthesis pathways regulate disease, but some of these pathways differ from those in mammals and may provide new drug targets. Two different pathways synthesize PE in C. albicans. The de novo pathway synthesizes PE from PS, which itself is synthesized by only one enzyme, Cho1p. In addition, the Kennedy pathway makes PE from extracellular ethanolamine. Mutants completely blocked in de novo PS and/or PE synthesis (cho1¿/¿ and psd1¿/¿ psd2¿/¿, respectively) are avirulent, have a significant drop in PE, expose cell wall ¿-glucans (an immune marker for fungal infections) to enhanced detection by the immune system, and adhere to invade host epithelial cells poorly. In addition, these mutants are ethanolamine auxotrophs, and it is possible that the mutants suffer a fitness defect in the host due to insufficient ethanolamine supplies. It s hypothesized that mutations that completely block the de novo PE synthesis pathway affect virulence by compromising cell signaling cascades within the cell, resulting in drastic changes in presentation of cell surface proteins involved in host adherence and immune evasion. These changes in PE synthesis may also decrease fitness of C. albicans in the host due to ethanolamine auxotrophy. This hypothesis will be tested in three aims: 1) Observe differences in cell signaling pathways known to be involved in the regulation of virulence and adherence to host tissues (ie. Rim101 pathway), 2) Determine if PS and PE play a role in evading the immune response 3) Discover if auxotrophy for ethanolamine, a known substrate of PE, affects virulence of the mutants in the host.