Systemic immune modulation by enteric commensal fungi

 描述(申请人提供)：越来越多的人认识到肠道共生微生物和哺乳动物宿主之间的共生促进了系统免疫细胞的激活，以及肠道组织的动态平衡。相反，肠道共生细菌组成的紊乱始终与肠道和全身炎症障碍以及肠道外组织感染的易感性有关。这些免疫调节特性是由宿主受体对共生细菌产物的识别推动的，宿主受体也启动了对病原体感染的固有宿主防御。因此，肠道共生微生物的紧张性刺激赋予了强大的全身免疫调节特性，可用于治疗微调免疫反应的激活。然而，由于在表征共生微生物的免疫调节特性方面几乎完全集中在肠道细菌上，非细菌共生微生物(如真菌、病毒)与哺乳动物宿主之间的共生关系仍然没有明确的定义。为了解决这些关键的知识空白，我们开发了一种创新的模型，通过用白色念珠菌重新克隆耗尽肠道细菌的小鼠来研究肠道共生真菌的免疫调节特性。在抗生素诱导肠道共生菌被根除后，口服白念珠菌接种会导致整个肠道长时间的高密度重新定植。我们的初步研究表明，白色念珠菌的定植消除了肠道共生细菌耗尽后发生的肠道损伤和炎症的易感性。这些结果与最近的研究结果平行，表明与肠道诺沃克病毒的单一定植可以取代共生细菌，以对抗异常的肠道炎症，并且共同表明，肠道真菌或病毒的紧张性刺激可以有效地绕过对肠道共生细菌的需要，以维持肠道的动态平衡。与此同时，这些发现也暴露了一些令人兴奋的新问题，涉及非细菌共生微生物如何校准系统免疫细胞的反应性，如何逃避防止肠道炎症的抗原特异性免疫细胞的激活，以及感知共生真菌的宿主细胞受体如何促进肠道和系统免疫转变。探索性研究将独特地结合尖端免疫学、转基因小鼠和重组微生物工具，旨在揭示共生肠道真菌与哺乳动物宿主之间的共生关系的这些基本问题，将在下列特定目标中解决：建立由共生肠道真菌控制的系统免疫细胞反应性的转变(目标1)；确定共生白色念珠菌特异性T细胞的分化和激活特性(目标2)；以及确定共生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(目标3)进行宿主感知。

 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).