A Nonribosomal Peptide Synthase Gene Driving Virulence in Mycobacterium tuberculosis.
A Nonribosomal Peptide Synthase Gene Driving Virulence in Mycobacterium tuberculosis.
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DOI：
10.1128/msphere.00352-18
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发表时间：
2018-10-31
期刊：
影响因子：
4.8
通讯作者：
Saraiva M
中科院分区：
文献类型：
--
作者：
Bhatt K;Machado H;Osório NS;Sousa J;Cardoso F;Magalhães C;Chen B;Chen M;Kim J;Singh A;Ferreira CM;Castro AG;Torrado E;Jacobs WR Jr;Bhatt A;Saraiva M
2016年，有超过1000万人患上结核病，180多万人死于这种疾病。这些数字使结核病成为全世界第九大死亡原因，也是单一传染病的主要原因。因此，在引起大多数人类结核病病例的病原体结核分枝杆菌中寻找新的治疗靶点至关重要。在这项研究中，我们揭示了结核分枝杆菌的一个新的毒力因子，nrp基因。在小鼠模型中，缺乏nrp可大大缩短结核分枝杆菌感染的病程，这在免疫缺陷宿主中尤为重要。这是非常相关的，因为结核病特别发生在免疫抑制的个体中，如艾滋病毒患者。非核糖体肽合成酶产生短肽的方式不同于经典的mrna依赖核糖体介导的翻译。结核分枝杆菌基因组中含有一个非核糖体肽合成酶基因nrp，这是一个被认为参与异腈脂肽生物合成的基因簇的一部分。在其他生长缓慢的致病性分枝杆菌和放线菌中发现同源簇。为了探讨nrp基因在感染中的作用，我们在结核分枝杆菌H37Rv中产生了一个nrp缺失突变体，并在免疫活性（C57BL/6）小鼠中检测了其毒力。nrp突变株在肺部表现出较低的初始生长速率，并且在感染小鼠的脾脏中传播有缺陷。感染突变菌株的小鼠的存活时间是感染野生型结核分枝杆菌的小鼠的两倍，而且值得注意的是，尽管在感染的后期阶段细菌负荷相似，但它们的病理表现较弱。野生型和nrp突变株在感染过程中的差异伴随着不同的免疫反应动力学。最引人注目的是，nrp突变体在免疫缺陷（SCID-、重组激活2 [RAG2]-和γ干扰素[IFN-γ]-缺陷）小鼠中被高度减弱，这表明巨噬细胞控制nrp突变体比控制野生型菌株更有效。然而，在IFN-γ存在的情况下，两种菌株同样受到控制。我们提出nrp基因及其相关簇是感染早期毒力的驱动因素。2016年，超过1000万人患上结核病，180多万人死于这种疾病。这些数字使结核病成为全世界第九大死亡原因，也是单一传染病的主要原因。因此，在引起大多数人类结核病病例的病原体结核分枝杆菌中寻找新的治疗靶点至关重要。在这项研究中，我们揭示了结核分枝杆菌的一个新的毒力因子，nrp基因。在小鼠模型中，缺乏nrp可大大缩短结核分枝杆菌感染的病程，这在免疫缺陷宿主中尤为重要。这是非常相关的，因为结核病特别发生在免疫抑制的个体中，如艾滋病毒患者。
Over 10 million people developed tuberculosis (TB) in 2016, and over 1.8 million individuals succumbed to the disease. These numbers make TB the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Therefore, finding novel therapeutic targets in Mycobacterium tuberculosis, the pathogen that causes most cases of human TB, is critical. In this study, we reveal a novel virulence factor in M. tuberculosis, the nrp gene. The lack of nrp highly attenuates the course of M. tuberculosis infection in the mouse model, which is particularly relevant in immune-deficient hosts. This is very relevant as TB is particularly incident in immune-suppressed individuals, such as HIV patients. Nonribosomal peptide synthases produce short peptides in a manner that is distinct from classical mRNA-dependent ribosome-mediated translation. The Mycobacterium tuberculosis genome harbors a nonribosomal peptide synthase gene, nrp, which is part of a gene cluster proposed to be involved in the biosynthesis of isonitrile lipopeptides. Orthologous clusters are found in other slow-growing pathogenic mycobacteria and actinomycetes. To probe the role of the nrp gene in infection, we generated an nrp deletion mutant in M. tuberculosis H37Rv and tested its virulence in immunocompetent (C57BL/6) mice. The nrp mutant strain displayed lower initial growth rates in the lungs and a defective dissemination to the spleens of infected mice. Mice infected with the mutant strain also survived for twice as long as those infected with wild-type M. tuberculosis and, remarkably, showed subdued pathology, despite similar bacterial loads at later stages of infection. The differences in the course of infection between wild-type and nrp mutant strains were accompanied by distinct dynamics of the immune response. Most strikingly, the nrp mutant was highly attenuated in immunodeficient (SCID-, recombination activating 2 [RAG2]-, and gamma interferon [IFN-γ]-deficient) mice, suggesting that macrophages control the nrp mutant more efficiently than they control the wild-type strain. However, in the presence of IFN-γ, both strains were equally controlled. We propose that the nrp gene and its associated cluster are drivers of virulence during the early stages of infection. IMPORTANCE Over 10 million people developed tuberculosis (TB) in 2016, and over 1.8 million individuals succumbed to the disease. These numbers make TB the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Therefore, finding novel therapeutic targets in Mycobacterium tuberculosis, the pathogen that causes most cases of human TB, is critical. In this study, we reveal a novel virulence factor in M. tuberculosis, the nrp gene. The lack of nrp highly attenuates the course of M. tuberculosis infection in the mouse model, which is particularly relevant in immune-deficient hosts. This is very relevant as TB is particularly incident in immune-suppressed individuals, such as HIV patients.