VapBC22 toxin-antitoxin system from Mycobacterium tuberculosis is required for pathogenesis and modulation of host immune response
VapBC22 toxin-antitoxin system from Mycobacterium tuberculosis is required for pathogenesis and modulation of host immune response
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DOI：
10.1126/sciadv.aba6944
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发表时间：
2020-06-01
期刊：
影响因子：
13.6
通讯作者：
Singh, Ramandeep
中科院分区：
文献类型：
--
作者：
Agarwal, Sakshi;Sharma, Arun;Singh, Ramandeep
毒力相关蛋白B和C毒素-抗毒素（TA）系统广泛存在于原核生物中，但它们在生理学中的确切作用知之甚少。我们已经从结核分枝杆菌的VapBC 22 TA系统的功能特点。转录组分析显示VapC 22毒素在M.结核病导致代谢酶水平降低和核糖体蛋白水平升高。蛋白质组学研究表明，在Delta vapC 22突变株中，毒性相关蛋白的表达减少，同源抗毒素VapB 22的水平增加。此外，Δ vapC 22突变株和VapB 22过表达株的M.结核杆菌在暴露于氧化应激时易于被杀死，并且在豚鼠和小鼠中显示出减弱的生长。宿主转录组分析表明，在感染Delta vapC 22突变株的小鼠中，参与先天免疫应答和组织重塑的转录物上调。总之，我们证明VapBC 22 TA系统属于一个关键的调控网络，是必不可少的M。结核病发病机制
Virulence-associated protein B and C toxin-antitoxin (TA) systems are widespread in prokaryotes, but their precise role in physiology is poorly understood. We have functionally characterized the VapBC22 TA system from Mycobacterium tuberculosis. Transcriptome analysis revealed that overexpression of VapC22 toxin in M. tuberculosis results in reduced levels of metabolic enzymes and increased levels of ribosomal proteins. Proteomics studies showed reduced expression of virulence-associated proteins and increased levels of cognate antitoxin, VapB22 in the Delta vapC22 mutant strain. Furthermore, both the Delta vapC22 mutant and VapB22 overexpression strains of M. tuberculosis were susceptible to killing upon exposure to oxidative stress and showed attenuated growth in guinea pigs and mice. Host transcriptome analysis suggests upregulation of the transcripts involved in innate immune responses and tissue remodeling in mice infected with the Delta vapC22 mutant strain. Together, we demonstrate that the VapBC22 TA system belongs to a key regulatory network and is essential for M. tuberculosis pathogenesis.