Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator
Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator
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DOI：
10.1073/pnas.1406693111
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发表时间：
2014-08-05
影响因子：
11.1
通讯作者：
Guilhot, Christophe
中科院分区：
文献类型：
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作者：
Gonzalo-Asensio, Jesus;Malaga, Wladimir;Guilhot, Christophe
虽然牛结核病（TB）病原体牛分枝杆菌（Mycobacterium bovis）可能感染人类并引起疾病，但长期流行病学数据表明，人类是一种溢出宿主，其中感染牛分枝杆菌（Mycobacterium bovis）可能会导致人类感染结核病。牛不能自我维持。事实上，M.牛菌株和其他动物谱系成员的结核杆菌非常罕见。在这里，我们报告了三个突变影响的双组分毒力调节系统PhoP/PhoR（PhoPR）在M。牛分枝杆菌和紧密连锁的非洲分枝杆菌谱系6（L 6），这可能解释了这种差异。将这些突变基因转移到人类结核病病原体结核分枝杆菌中，导致PhoP调节子下调，生物活性脂质丧失，6-kDa早期抗原靶标（ESAT-6）分泌减少，毒力降低。值得注意的是，phoPR突变的有害影响部分被动物适应性和M. Africanum L 6谱系，其通过PhoPR非依赖性机制恢复ESAT-6分泌。类似地，我们还观察到在phoPR基因座上游插入IS 6110元件可以完全恢复phoPR-牛相关的适应性丧失，这是异常M的情况。西班牙爆发的牛流感病毒。我们的研究结果最终解释了长期流行病学数据，表明M。牛和相关的phoPR突变菌株对发展为明显的人类TB的风险较低，对TB的进化史具有重大影响。
Although the bovine tuberculosis (TB) agent, Mycobacterium bovis, may infect humans and cause disease, long-term epidemiological data indicate that humans represent a spill-over host in which infection with M. bovis is not self-maintaining. Indeed, human-to-human transmission of M. bovis strains and other members of the animal lineage of the tubercle bacilli is very rare. Here, we report on three mutations affecting the two-component virulence regulation system PhoP/PhoR (PhoPR) in M. bovis and in the closely linked Mycobacterium africanum lineage 6 (L6) that likely account for this discrepancy. Genetic transfer of these mutations into the human TB agent, Mycobacterium tuberculosis, resulted in down-regulation of the PhoP regulon, with loss of biologically active lipids, reduced secretion of the 6-kDa early antigenic target (ESAT-6), and lower virulence. Remarkably, the deleterious effects of the phoPR mutations were partly compensated by a deletion, specific to the animal-adapted and M. africanum L6 lineages, that restores ESAT-6 secretion by a PhoPR-independent mechanism. Similarly, we also observed that insertion of an IS6110 element upstream of the phoPR locus may completely revert the phoPR-bovis-associated fitness loss, which is the case for an exceptional M. bovis human outbreak strain from Spain. Our findings ultimately explain the long-term epidemiological data, suggesting that M. bovis and related phoPR-mutated strains pose a lower risk for progression to overt human TB, with major impact on the evolutionary history of TB.