PDF(Pubmed)
Abstract：
The genome of Mycobacterium tuberculosis encodes for a large repertoire of toxin-antitoxin systems. In the present study, MenT3 and MenT4 toxins belonging to MenAT subfamily of TA systems have been functionally characterized. We demonstrate that ectopic expression of these toxins inhibits bacterial growth and this is rescued upon co-expression of their cognate antitoxins. Here, we show that simultaneous deletion of menT3 and menT4 results in enhanced susceptibility of M. tuberculosis upon exposure to oxidative stress and attenuated growth in guinea pigs and mice. We observed reduced expression of transcripts encoding for proteins that are essential or required for intracellular growth in mid-log phase cultures of ΔmenT4ΔT3 compared to parental strain. Further, the transcript levels of proteins involved in efficient bacterial clearance were increased in lung tissues of ΔmenT4ΔT3 infected mice relative to parental strain infected mice. We show that immunization of mice and guinea pigs with ΔmenT4ΔT3 confers significant protection against M. tuberculosis infection. Remarkably, immunization of mice with ΔmenT4ΔT3 results in increased antigen-specific TH1 bias and activated memory T cell response. We conclude that MenT3 and MenT4 are important for M. tuberculosis pathogenicity and strains lacking menT3 and menT4 have the potential to be explored further as vaccine candidates.
摘要：
结核分枝杆菌的基因组编码大量的毒素-抗毒素系统。在本研究中,已经对属于TA系统的MenAT亚家族的MenT3和MenT4毒素进行了功能表征。我们证明了这些毒素的异位表达抑制了细菌的生长，这在它们的同源抗毒素共表达后得以挽救。这里,我们表明，同时缺失menT3和menT4导致暴露于氧化应激后，豚鼠和小鼠的结核分枝杆菌易感性增强，生长减弱。我们观察到，与亲本菌株相比，在ΔmenT4ΔT3的对数中期培养物中，编码细胞内生长必需或必需的蛋白质的转录本表达降低。Further,与亲本菌株感染的小鼠相比，ΔmenT4ΔT3感染的小鼠的肺组织中涉及有效细菌清除的蛋白质的转录水平增加。我们表明，用ΔmenT4ΔT3免疫小鼠和豚鼠可提供对结核分枝杆菌感染的显着保护。值得注意的是,用ΔmenT4ΔT3免疫小鼠导致增加的抗原特异性TH1偏倚和激活的记忆T细胞应答。我们得出的结论是，MenT3和MenT4对结核分枝杆菌致病性很重要，缺乏menT3和menT4的菌株有可能作为候选疫苗进一步探索。
