Gaucher disease protects against tuberculosis.
Gaucher disease protects against tuberculosis.
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DOI：
10.1073/pnas.2217673120
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发表时间：
2023-02-14
影响因子：
11.1
通讯作者：
Ramakrishnan L
中科院分区：
文献类型：
--
作者：
Fan J;Hale VL;Lelieveld LT;Whitworth LJ;Busch-Nentwich EM;Troll M;Edelstein PH;Cox TM;Roca FJ;Aerts JMFG;Ramakrishnan L
高谢病是一种隐性遗传性疾病，脂类物质葡萄糖神经酰胺和葡萄糖鞘氨醇积聚在巨噬细胞的溶酶体内。巨噬细胞是第一个吞噬感染细菌的免疫细胞，我们发现葡萄糖鞘氨醇增强了它们杀死导致结核病的结核分枝杆菌的能力。由于特定突变导致的高谢病在德系犹太人中很常见。由于从中世纪开始，他们经常被限制在结核病高发地区，有人提出，这种突变之所以盛行，是因为杂合子受到了保护，这些杂合子既不会积累脂质，也不会表现出高谢病。我们的发现提高了对表现为轻度高谢病的纯合子进行选择的可能性，这些纯合子对结核病具有保护作用，而结核病往往是致命的。葡萄糖脑苷酶(GBA1)基因的双等位基因突变导致高谢病，其特征是溶酶体在巨噬细胞中积累葡萄糖神经酰胺和葡萄糖鞘氨醇。高雪病和其他溶酶体疾病在德系犹太人中高发。有人提出，潜在的突变赋予了选择性优势，特别是提供了对结核病的保护。在这里，使用斑马鱼高谢病模型，我们发现突变GBA1 N370S，在德系犹太人中占主导地位，通过巨噬细胞溶酶体中葡萄糖鞘氨醇的杀菌活性增加对结核病的抵抗力。与仅在纯合子中发生的溶酶体积聚一致，杂合子仍易患结核病。因此，我们的发现揭示了GBA1 N370S预防结核病的机制基础，并为选择GBA1 N370S提供了生物学上的合理性，如果对纯合子的相对温和的有害影响被对结核病的显著保护所抵消，结核病是一种从中世纪到19世纪在欧洲肆虐的年轻人杀手。
Gaucher disease is a recessively inherited disorder in which the lipids glucosylceramide and glucosylsphingosine accumulate in lysosomes of macrophages. Macrophages are the first immune cells to engulf infecting bacteria, and we find that glucosylsphingosine increases their ability to kill Mycobacterium tuberculosis that causes tuberculosis.Gaucher disease due to a particular mutation is frequent in Ashkenazi Jews. Since from the middle ages they were often confined to areas of high tuberculosis prevalence, it has been proposed that the mutation prevailed because heterozygotes, who do not accumulate lipids or manifest Gaucher disease, were protected. Our findings raise the possibility that selection operated on homozygotes manifesting mild forms of Gaucher disease who were protected against tuberculosis which would often have been fatal. Biallelic mutations in the glucocerebrosidase (GBA1) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. Gaucher and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by GBA1 N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century.
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影响因子：
2.7
作者：
Fischer CL;Walters KS;Drake DR;Blanchette DR;Dawson DV;Brogden KA;Wertz PW
通讯作者：
Wertz PW
影响因子：
--
作者：
Donovan, Joseph;Phu, Nguyen Hoan;Thwaites, Guy E
通讯作者：
Thwaites, Guy E
影响因子：
32.4
作者：
Cambier CJ;O'Leary SM;O'Sullivan MP;Keane J;Ramakrishnan L
通讯作者：
Ramakrishnan L
由巨噬细胞诱导的外排机制介导的复制分枝杆菌的药物耐受性。
影响因子：
64.5
作者：
Adams KN;Takaki K;Connolly LE;Wiedenhoft H;Winglee K;Humbert O;Edelstein PH;Cosma CL;Ramakrishnan L
通讯作者：
Ramakrishnan L
影响因子：
3.5
作者：
Ferraz, Maria J.;Marques, Andre R. A.;Aerts, Johannes M.
通讯作者：
Aerts, Johannes M.