Role of phosphatidylethanolamine in regulating virulence in Candida albicans

描述（由申请人提供）：念珠菌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，这是一种感染，影响患有获得性免疫缺陷综合征（艾滋病）的患者和其他疾病。念珠菌也是重症监护病房中全身性感染的第四大常见原因（死亡率约30%）。本研究建议探讨磷脂磷脂（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需的毒力因子，以及逃避宿主免疫反应。磷脂合成途径如何调节疾病尚不清楚，但其中一些途径与哺乳动物不同，可能提供新的药物靶点。在白色念珠菌中有两种不同的途径合成PE。新途径从PS合成PE，而PS本身仅由一种酶Cho1p合成。此外，肯尼迪途径从细胞外乙醇胺制造PE。完全阻断新生PS和/或PE合成的突变体（分别为cho1¿/¿和psd1¿/¿psd2¿/¿）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缺乏症，这是可能的

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.