Deficiency in the glycosyltransferase Gcnt1 increases susceptibility to tuberculosis through a mechanism involving neutrophils
Deficiency in the glycosyltransferase Gcnt1 increases susceptibility to tuberculosis through a mechanism involving neutrophils
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DOI：
10.1038/s41385-020-0277-7
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发表时间：
2020-03-13
影响因子：
8
通讯作者：
Saraiva, Margarida
中科院分区：
文献类型：
--
作者：
Fonseca, Kaori L.;Maceiras, Ana Raquel;Saraiva, Margarida
聚糖对免疫和疾病的调节作用越来越被人们所认识。然而，宿主糖基化如何形成以及结核病如何形成仍然知之甚少。我们发现，缺乏氨基葡萄糖（N-乙酰基）转移酶1（Gcnt 1），核心-2 O-聚糖生物合成的关键酶，驱动结核分枝杆菌感染的易感性。Gcnt 1缺陷小鼠的易感性增加的特征在于广泛的肺免疫病理学，机制上与中性粒细胞相关。未感染的Gcnt 1缺陷小鼠表现出骨髓、血液和肺嗜中性粒细胞，并随着感染进一步增加。血液嗜中性粒细胞需要Gcnt 1缺乏的造血室，与增强粒细胞生成，但正常的细胞从骨髓中排出。有趣的是，血液嗜中性粒细胞转化为对M。结核感染时，间质中Gnct 1缺陷也是必要的。完全Gcnt 1缺乏与肺中性粒细胞趋化因子CXCL 2表达增加相关最后，我们证明了各种糖基转移酶编码基因的转录水平在活动性结核病患者的全血中发生了改变，并且在结核病患者的肺中检测到唾液酸刘易斯x，一种广泛存在于人类中性粒细胞中的聚糖。我们的研究结果揭示了Gcnt 1、嗜中性粒细胞和对M.结核病感染，发现新的球员平衡结核病的免疫反应。
Modulation of immunity and disease by glycans is increasingly recognized. However, how host glycosylation shapes and is shaped by tuberculosis remains poorly understood. We show that deficiency in the glucosaminyl (N-acetyl) transferase 1 (Gcnt1), a key enzyme for core-2 O-glycans biosynthesis, drives susceptibility to Mycobacterium tuberculosis infection. The increased susceptibility of Gcnt1 deficient mice was characterized by extensive lung immune pathology, mechanistically related to neutrophils. Uninfected Gcnt1 deficient mice presented bone marrow, blood and lung neutrophilia, which further increased with infection. Blood neutrophilia required Gcnt1 deficiency in the hematopoietic compartment, relating with enhanced granulopoiesis, but normal cellular egress from the bone marrow. Interestingly, for the blood neutrophilia to translate into susceptibility to M. tuberculosis infection, Gnct1 deficiency in the stroma was also necessary. Complete Gcnt1 deficiency associated with increased lung expression of the neutrophil chemoattractant CXCL2. Lastly, we demonstrate that the transcript levels of various glycosyltransferase-encoding genes were altered in whole blood of active tuberculosis patients and that sialyl Lewis x, a glycan widely present in human neutrophils, was detected in the lung of tuberculosis patients. Our findings reveal a previously unappreciated link between Gcnt1, neutrophilia and susceptibility to M. tuberculosis infection, uncovering new players balancing the immune response in tuberculosis.