Newton Sandra M, Smith Rebecca J, Wilkinson Katalin A, Nicol Mark P, Garton Natalie J, Staples Karl J, Stewart Graham R, Wain John R, Martineau Adrian R, Fandrich Sarah, Smallie Timothy, Foxwell Brian, Al-Obaidi Ahmed, Shafi Jamila, Rajakumar Kumar, Kampmann Beate, Andrew Peter W, Ziegler-Heitbrock Loems, Barer Michael R, Wilkinson Robert J
Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom.
Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15594-8. doi: 10.1073/pnas.0604283103. Epub 2006 Oct 6.
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.
结核分枝杆菌的六个主要谱系似乎在不同种族群体中优先传播。我们在CH菌株中发现了一个影响Rv1519的缺失，CH菌株是从英国莱斯特的一次大规模疫情中分离出来的，巧合的是，它定义了与该市一个主要种族群体相匹配的东非-印度谱系。在肉汤培养基中，CH的生长速度比参考测序菌株（CDC1551和H37Rv）慢，酸性更低，对H2O2的耐受性也更低。然而，CH在人单核细胞衍生巨噬细胞中的生长能力并未受损。与CDC1551和H37Rv相比，CH诱导单核细胞衍生巨噬细胞产生的保护性IL-12p40较少，而抗炎性IL-10和IL-6的基因转录和分泌较多。因此，CH似乎通过将先天反应偏向吞噬细胞失活来补偿微生物学上的衰减。与模式菌株H37Rv相比，CH缺失的九个额外基因中，只有Rv1519的互补逆转了CH诱导巨噬细胞产生抗炎性IL-10的能力。结核分枝杆菌中的Rv1519多态性赋予了一种免疫颠覆表型，这有助于该谱系的持续存在和爆发潜力。
