A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion
A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion
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DOI：
10.1073/pnas.0604283103
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发表时间：
2006-10-17
影响因子：
11.1
通讯作者：
Wilkinson, Robert J.
中科院分区：
文献类型：
--
作者：
Newton, Sandra M.;Smith, Rebecca J.;Wilkinson, Robert J.
结核分枝杆菌的六个主要谱系似乎在不同的种族群体中优先传播。我们在CH中发现了一个影响Rv1519的缺失，这是一种从英国莱斯特大爆发中分离出来的毒株，巧合地定义了与这个城市的一个主要种族群体相匹配的东非-印度血统。与参考测序菌株(CDC1551和H37Rv)相比，CH在发酵液中的生长速度较慢，酸性和对过氧化氢的耐受性较差。然而，CH在人单核细胞来源的巨噬细胞中的生长能力并未受到损害。与CDC1551和H37Rv相比，CH诱导的单核巨噬细胞保护性IL-12p40减少，抗炎IL-10和IL-6基因转录和分泌增加。因此，CH似乎通过扭曲吞噬细胞失活的先天反应来补偿微生物的衰减。Rv1519的互补，但与模式株H37Rv相比，CH缺失的9个额外基因都不能逆转CH诱导巨噬细胞产生抗炎IL-10的能力。结核分枝杆菌Rv1519基因的多态赋予了一种免疫颠覆性表型，这种表型有助于该家族的持久性和爆发潜力。
Six major lineages of Mycobacterium tuberculosis appear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affecting Rv1519 in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H2O2-tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation of Rv1519, but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. The Rv1519 polymorphism in M. tuberculosis confers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage.