Systemic immune modulation by enteric commensal fungi

 描述（由申请人提供）：越来越多地认识到肠道微生物和哺乳动物宿主之间的共生关系促进全身免疫细胞活化，沿着肠组织稳态。相反，肠道细菌组成的破坏始终与肠道和全身性炎症性疾病相关，沿着肠外组织对感染的易感性。这些免疫调节特性是由宿主受体识别肠道细菌产物驱动的，所述宿主受体也启动针对病原性感染的先天宿主防御。因此，肠道微生物的紧张刺激赋予有效的全身免疫调节特性，其可用于免疫应答的治疗性微调激活。尽管如此，考虑到在表征肠道微生物的免疫调节特性时几乎只关注肠道细菌，非细菌肠道微生物（例如真菌、病毒）与哺乳动物宿主之间的共生关系仍然定义不清。为了解决这些关键的知识差距，我们开发了一种创新的模型，通过用白色念珠菌对肠道细菌耗尽的小鼠进行体外培养来研究肠道真菌的免疫调节特性。在抗生素诱导的肠道寄生菌根除后，口服白色念珠菌接种导致整个肠道长时间的高密度再定植。我们的初步研究表明，白色念珠菌定植消除了肠道损伤和炎症的易感性，发生后，消耗肠道细菌。这些结果与最近的发现平行，表明肠道诺如病毒的单定殖可以取代肠道细菌以保护免受异常肠道炎症，并且一起表明肠道真菌或病毒的滋补刺激可以各自有效地绕过维持肠道稳态对肠道细菌的需要。与此同时，这些发现还揭示了令人兴奋的新问题，即非细菌肠道微生物如何校准全身免疫细胞的反应性，逃避防止肠道炎症的抗原特异性免疫细胞的激活，以及感知肠道真菌的宿主细胞受体促进肠道和全身免疫变化。探索性研究独特地结合了联合收割机尖端的免疫学、转基因小鼠和重组微生物工具，旨在阐明关于肠道真菌和哺乳动物宿主之间共生关系的这些基本问题，这些研究将在以下具体目标中得到解决：建立由肠道真菌控制的全身免疫细胞反应性的变化（目标1）;确定真菌白念珠菌特异性T细胞的分化和活化特性（目标2）;确定真菌的免疫调节是否需要通过β-葡聚糖模式识别受体dectin-1进行宿主感知（目标3）。

 DESCRIPTION (provided by applicant): Increasingly recognized symbiosis between enteric commensal microbes and the mammalian host promotes systemic immune cell activation, along with intestinal tissue homeostasis. Conversely, disruptions in the composition of intestinal commensal bacteria are consistently linked with intestinal and systemic inflammatory disorders, along with susceptibility to infection in extra-intestinal tissues. These immune modulatory properties are driven by recognition of commensal bacterial products through host receptors that also initiate innate host defense against pathogenic infection. Thus, tonic stimulation by intestinal commensal microbes confers potent systemic immune modulatory properties that can be exploited for therapeutically fine- tuning activation of immune responses. Nonetheless, given the near exclusive focus on intestinal bacteria in characterizing the immune modulatory properties of commensal microbes, the symbiotic relationship between non-bacterial commensal microbes (e.g. fungi, viruses) and mammalian host remain poorly defined. To address these critical gaps in knowledge, we developed an innovative model to investigate the immune modulatory properties of enteric commensal fungi by recolonizing mice depleted of intestinal bacteria with Candida albicans. Following antibiotic induced eradication of enteric commensal bacteria, oral Candida albicans inoculation results in prolonged high-density re-colonization throughout the intestinal tract. Our initial studies show Candida albicans colonization eliminates susceptibility to intestinal injury and inflammation that occurs after depletion of intestinal commensal bacteria. These results parallel recent findings demonstrating mono-colonization with enteric norovirus can replace commensal bacteria in protection against aberrant intestinal inflammation, and together indicate tonic stimulation by intestinal fungi or viruses can each efficiently bypass the need for enteric commensal bacteria in maintaining intestinal homeostasis. At the same time, these findings also expose exciting new questions with regards to how non-bacterial commensal microbes calibrate responsiveness of systemic immune cells, evade activation of antigen-specific immune cells that prevents intestinal inflammation, and host cell receptors that sense commensal fungi in promoting intestinal and systemic immunological shifts. Exploratory studies that uniquely combine cutting edge immunological, transgenic mouse, and recombinant microbial tools designed to shed light on these fundamental questions regarding the symbiotic relationship between commensal enteric fungi and mammalian host will be addressed in the following specific aims: establish shifts in systemic immune cell responsiveness controlled by commensal enteric fungi (Aim 1); identify differentiation and activation properties for commensal Candida albicans specific T cells (Aim 2); and determine whether immune modulation by commensal fungi requires host sensing through the beta-glucan pattern-recognition receptor, dectin-1 (Aim 3).