Commensal Candida albicans primed Th17 immunity

抽象的。人类肠道中估计有100万亿个微生物，这些微生物越来越多地被认为是 通过强化免疫刺激促进健康。这些包括无害的海藻微生物沿着 致病微生物-能够引起肠道生态失调或侵入性感染的微生物。我们目前所了解的大部分 从细菌的透镜来评价宿主-微生物共生关系。然而，来自 包括真核生物在内的其他分类学领域也普遍存在于粘膜组织中，但我们 了解这些微生物如何建立免疫系统并驱动免疫学变化仍然是 基本的这种知识上的差距对于最常见的真菌致病菌念珠菌尤为重要 白色念珠菌，它可以易位出胃肠道（GI），并导致危及生命的全身感染， 特别是在免疫功能低下的个体中。为了解决这些知识上的根本差距， 模型C.在小鼠中形成白色念珠菌肠定殖。重组C.白色念珠菌细胞 工程化以表达确定的模型抗原并用于建立定殖，使得具有替代抗原的T细胞 C.可鉴定白色念珠菌特异性。利用该模型，我们证明了C.白色念珠菌细胞定植于胃肠道 导致远距离作用-它们驱动真菌特异性Th17 CD4 + T细胞的全身积累。这些 T细胞与IL-17和活化的中性粒细胞一起工作，通过以下方式提供针对全身感染的保护： C.白色念珠菌以及细胞外细菌病原体。这些结果突出了 克鲁萨尔角白色念珠菌细胞居住在胃肠道，并建议与这个物种的共同进化导致了一个 互惠互利的关系。然而，重要的问题仍然是如何C。肠道中的白色念珠菌细胞 全身免疫反应，以及如何在没有过度炎症的情况下触发Th17信号。这条线 研究的基础上产生的令人兴奋的初步数据共同博士的实验室路和博士。 班尼特，两位在临床传染病/细胞免疫学方面具有互补专长的研究人员， 真菌学/真菌发病机理。这项建议将涉及分子和细胞机制 其中C.白色念珠菌细胞与粘膜宿主组织相互作用， 具体目标如下：（1）明确C.白色念珠菌形态学变化驱动全身性Th17免疫，（2） 建立引发系统性Th17免疫的真菌配体和宿主模式识别受体，和（3） 研究活性氧和Duox 2（双氧化酶2）在局部和Th17免疫启动中的作用 由c.白色念珠菌细胞这些具体目标中的每一个都得到了广泛的已发表和未发表的初步研究的支持。 数据这些目标的成功实现将阐明真菌真菌与植物之间重要的共生关系， 和哺乳动物宿主，以及负责通过肠道引发系统性Th17免疫的机制 刺激.

Abstract. The human intestine harbors an estimated 100 trillion microbes that are increasingly recognized to promote health through tonic immune stimulation. These include innocuous commensal microbes along with pathobionts - those capable of causing gut dysbiosis or invasive infection. Most of what we currently understand about host-microbe commensalism has been evaluated through the lens of bacteria. However, microbes from other taxonomic domains, including eukaryotes, also ubiquitously colonize mucosal tissues and yet our understanding of how these microbes establish commensalism and drive immunological changes remains rudimentary. This gap in knowledge is especially significant for the most common fungal pathobiont Candida albicans, which can translocate out of the gastrointestinal (GI) tract and cause life-threatening systemic infection, particularly in immunocompromised individuals. To address these fundamental gaps in knowledge, an instructive model of C. albicans intestinal colonization in mice was developed. Recombinant C. albicans cells were engineered to express defined model antigens and used to establish colonization so that T cells with surrogate C. albicans specificity could be identified. Using this model, we show that C. albicans cells colonizing the GI tract result in action at a distance - they drive the systemic accumulation of fungal-specific Th17 CD4+ T cells. These T cells work together with IL-17 and activated neutrophils to provide protection against a systemic infection by C. albicans as well as by extracellular bacterial pathogens. These results highlight the protective benefits of commensal C. albicans cells residing in the GI tract, and suggest that co-evolution with this species has led to a mutually beneficial relationship. However, important questions remain as to how C. albicans cells in the gut prime systemic immune responses, and how Th17 signals can be triggered without excessive inflammation. This line of investigation builds upon exciting preliminary data generated together by the laboratories of Dr. Way and Dr. Bennett, two investigators with complementary expertise in clinical infectious disease/cellular immunology and mycology/fungal pathogenesis, respectively. This proposal will address the molecular and cellular mechanisms by which C. albicans cells interact with mucosal host tissues to drive gut local and systemic immunity through the following specific aims: (1) Define how C. albicans morphological changes drive systemic Th17 immunity, (2) Establish the fungal ligand and host pattern recognition receptor(s) that prime systemic Th17 immunity, and (3) Investigate the role of reactive oxygen species and Duox2 (Dual Oxidase 2) for local and Th17 immunity primed by C. albicans cells. Each of these specific aims is supported by extensive published and unpublished preliminary data. Successful completion of these aims will shed light on the important symbiosis between fungal commensal and mammalian host, and the mechanisms responsible for priming systemic Th17 immunity through intestinal stimulation.