Novel Candida albicans host receptors during infection and immune response

摘要/总结 多态性真菌白色念珠菌是内源性人类真菌生物群的一部分。它寄居在粘膜上 30 - 70%的健康人的皮肤。这种真菌会导致浅表粘膜疾病和生命 威胁着侵入性感染口咽念珠菌病（OPC）在一个大的， 不同人群的患者，包括HIV/AIDS、干燥综合征、糖尿病、癌症患者 近1000万例艾滋病毒/艾滋病相关的OPC发生 这些病例中有近五分之一涉及食管。为引起OPC，C.白色念珠菌必须 粘附侵入口腔粘膜，抵抗宿主吞噬细胞的杀伤。斯威德格尔博士发现 EphA2是一种新的C.白色念珠菌EphA2 结合真菌细胞壁上暴露的β-葡聚糖，初步数据表明，它在 上皮细胞和中性粒细胞对生物体的反应。 该建议的中心目标是确定β-葡聚糖受体EphA2如何与其他受体相互作用。 宿主信号分子，以诱导口腔粘膜和白细胞中的炎症反应，并诱导 OPC期间口腔上皮细胞侵袭。目的1将评估EphA2活化和下游转录因子的作用。 在口腔C.体外和体内白念珠菌感染。目标2将描述 EphA2激活触发嗜中性粒细胞杀真菌活性的机制。长期目标是 研究的目的是确定宿主受体如何识别入侵的真菌并维持粘膜免疫， 可以开发治疗和预防真菌疾病的新药和策略。 候选人Swidergall博士对真菌学研究有着长期的兴趣。完成后 在K99的指导阶段，他的目标是成为一个领先的学术研究机构的助理教授。 他计划在该研究所继续研究关键宿主细胞受体在发病机制中的作用 OPC的。他还计划教学生和培养未来的科学家。本K99/R00提案旨在 补充Swidergall博士先前的研究培训，并为他提供必要的技术和 专业知识，成为独立调查员。他将在K99阶段接受的培训将 大大提高了他的职业前景，使他在顶级教师职位上具有很强的竞争力， 科研院所Swidergall博士的主要导师Scott G. Filler和共同导师Michael S.莱昂纳基斯， 他们的相关性，多样性和互补性的专业知识，以涵盖他的所有元素， 提议此外，Swidergall博士还组建了一个由不同科学家组成的咨询委员会， 监督他的科学进步和职业发展，在他过渡到一个独立的调查员。 该委员会的所有成员都是资深科学家，在指导博士后方面具有丰富的经验。

ABSTRACT/SUMMARY The polymorphic fungus, Candida albicans is part of the endogenous human mycobiota. It colonizes mucosal surfaces of 30-70% of healthy individuals. The fungus causes both superficial mucosal diseases and life threatening invasive infection. Oropharyngeal candidiasis (OPC) causes significant morbidity in a large and diverse population of patients, including those with HIV/AIDS, Sjogren's syndrome, diabetes mellitus, cancer of the head and neck, or the use of steroids Nearly 10 million cases of HIV/AIDS associated OPC occur annually and nearly one fifth of these cases have esophageal involvement. To cause OPC, C. albicans must adhere to and invade the oral mucosa, and resist being killed by host phagocytes. Dr. Swidergall discovered that EphA2 on oral epithelial cells and neutrophils is a novel pattern recognition receptor for C. albicans. EphA2 binds exposed β-glucan on the fungal cell walls, and the preliminary data indicate that it plays a key role in the response of both epithelial cells and neutrophils to the organism. The central objective of this proposal is to determine how the β-glucan receptor EphA2 interacts with other host signaling molecules to induce an inflammatory response in both the oral mucosa and leukocytes, and induce oral epithelial cell invasion during OPC. Aim 1 will evaluate the role of EphA2 activation and downstream signaling in oral epithelial cells during oral C. albicans infection in vitro and in vivo. Aim 2 will characterize the mechanisms by which EphA2 activation triggers neutrophil fungicidal activity. The long-term goal of this research is to determine how host receptors recognize invading fungi and maintain mucosal immunity so that new drugs and strategies to treat and prevent fungal diseases can be developed. The candidate, Dr. Swidergall, has a longstanding interest in mycology research. After completing the mentored phase of this K99, his goal is to become an assistant professor at a leading academic research institute, where he plans to continue his research on the role of critical host cell receptors in the pathogenesis of OPC. He also plans to teach students and train future scientists. This K99/R00 proposal is designed to complement Dr. Swidergall's prior research training and provide him with the necessary technical and intellectual expertise to become an independent investigator. The training he will receive in the K99 phase will substantially enhance his career prospects, and make him highly competitive for faculty positions in top research institutes. Dr. Swidergall's primary mentor, Dr. Scott G. Filler, and co-mentor, Dr. Michail S. Lionakis, were carefully selected for their relevant, diverse, and complementary expertise to cover all elements of his proposal. In addition, Dr. Swidergall has assembled an advisory committee of a diverse group of scientists to oversee his scientific progression and career development during his transition to an independent investigator. All members of this committee are senior scientists with extensive experience in mentoring postdocs.