An attenuated Mycobacterium tuberculosis clinical strain with a defect in ESX-1 secretion induces minimal host immune responses and pathology
An attenuated Mycobacterium tuberculosis clinical strain with a defect in ESX-1 secretion induces minimal host immune responses and pathology
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DOI：
10.1038/srep46666
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发表时间：
2017-04-24
影响因子：
4.6
通讯作者：
Aagaard, Claus
中科院分区：
文献类型：
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作者：
Clemmensen, Helena Strand;Knudsen, Niels Peter Hell;Aagaard, Claus
虽然结核分枝杆菌（M.tb）DK 9897是减毒株，它是从一名肺外结核患者中分离出来的，并接种了亚单位疫苗（H56）结核分枝杆菌DK 9897的减毒和缺乏保护都是因为它不能分泌EsxA毒力因子，也不能诱导宿主对它的反应。基因由于编码的EccCa 1蛋白为ESX-1分泌提供能量，因此表明ESX-1 VII型分泌系统存在缺陷。用携带结核分枝杆菌H37 Rv序列eccCa 1-eccCb 1-pe 35的质粒进行遗传互补，重新建立了EsxA分泌、宿主特异性EsxA T细胞应答和增加的菌株毒力。ESX-1分泌缺陷阻止了几种毒力因子在感染期间发挥作用，因此减弱了M. tb。它排除了针对强抗原的特异性T细胞应答，并且我们在结核分枝杆菌DK 9897感染动物的肺中发现了非常少的体内细胞因子产生、大体病理学或肉芽肿形成。这与结核分枝杆菌DK 9897不能破坏吞噬体膜并与胞质溶胶接触一致。
Although Mycobacterium tuberculosis (M.tb) DK9897 is an attenuated strain, it was isolated from a patient with extrapulmonary tuberculosis and vaccination with a subunit vaccine (H56) induced poor protection against it. Both attenuation and lack of protection are because M.tb DK9897 cannot secrete the EsxA virulence factor nor induce a host response against it. Genome sequencing identified a frameshift mutation in the eccCa1 gene. Since the encoded EccCa1 protein provides energy for ESX-1 secretion, it suggested a defect in the ESX-1 type VII secretion system. Genetic complementation with a plasmid carrying the M.tb H37Rv sequence of eccCa1-eccCb1-pe35re-established EsxA secretion, host specific EsxA T-cell responses, and increased strain virulence. The ESX-1 secretion defect prevents several virulence factors from being functional during infection and therefore attenuates M.tb. It precludes specific T-cell responses against strong antigens and we found very little in vivo cytokine production, gross pathology or granuloma formation in lungs from M.tb DK9897 infected animals. This coincides with M.tb DK9897 being unable to disrupt the phagosome membrane and make contact to the cytosol.