小柯机器人

美国康奈尔大学 Iliyan D. Iliev课题组近日取得一项新成果。他们发现了炎症性肠病中真菌菌株多样性的免疫调节。该项研究成果2022年3月16日在线发表于《自然》杂志上。

在这里，研究人员开发了一个转化平台，用于在真菌菌株和患者特异性水平上对真菌生物群进行功能分析。该平台结合了高分辨率真菌群测序、真菌培养组学和基因组学、基于 CRISPR-Cas9 的真菌菌株编辑系统、体外功能性免疫反应性测定和体内模型，能够检查人类肠道中的宿主-真菌串扰。研究人员发现，机会性白色念珠菌菌株具有丰富的遗传多样性，这些菌株在炎症性肠病患者的结肠粘膜中占主导地位。在这些人肠道来源的分离株中，具有高免疫细胞损伤能力的菌株（HD菌株）通过IL-1β依赖性机制反映了患有溃疡性结肠炎和体内肠道炎症加重的个体患者的疾病特征。

在肠道从良性共生状态向病原状态转变的过程中，HD菌株的肠道环境特异性炎症免疫和产生白细胞介素17A的T辅助细胞(TH17细胞)抗真菌反应依赖于白色念珠菌分泌的肽毒素念珠菌素。这些发现揭示了人类肠道中宿主-真菌相互作用的菌株特异性，并突出了炎症性疾病的新诊断和治疗靶点。

据悉，真菌微生物群(mycobiota)是哺乳动物胃肠道中复杂的多界微生物群落的组成部分，在免疫调节中发挥重要作用。尽管真菌菌群的异常变化与多种疾病有关，包括炎症性肠病，但目前尚不清楚通过深度测序捕获的真菌种类是否代表活生物体，以及特定真菌是否对受影响个体的疾病发展具有功能性影响。

附：英文原文

Title: Immune regulation by fungal strain diversity in inflammatory bowel disease

Author: Li, Xin V., Leonardi, Irina, Putzel, Gregory G., Semon, Alexa, Fiers, William D., Kusakabe, Takato, Lin, Woan-Yu, Gao, Iris H., Doron, Itai, Gutierrez-Guerrero, Alejandra, DeCelie, Meghan B., Carriche, Guilhermina M., Mesko, Marissa, Yang, Chen, Naglik, Julian R., Hube, Bernhard, Scherl, Ellen J., Iliev, Iliyan D.

Issue&Volume: 2022-03-16

Abstract: The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation1,2,3,4,5,6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3,4,5,6,7,8,9, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR–Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host–fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host–fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.

DOI: 10.1038/s41586-022-04502-w

Source: https://www.nature.com/articles/s41586-022-04502-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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