Predicting toxins found in toxin-antitoxin systems with a role in host-induced Burkholderia pseudomallei persistence.
Predicting toxins found in toxin-antitoxin systems with a role in host-induced Burkholderia pseudomallei persistence.
复制标题
DOI：
10.1038/s41598-020-73887-3
复制
发表时间：
2020-10-09
影响因子：
4.6
通讯作者：
Torres AG
中科院分区：
文献类型：
--
作者：
Ross BN;Thiriot JD;Wilson SM;Torres AG
假鼻疽伯克霍尔德氏菌(BPM)是一种引起类梅毒的细菌病原体，即使使用抗生素治疗，该病的死亡率高达40%，感染复发率为15%-23%。抗生素对BPM的无效清除被认为是由于持久性，一种冬眠样的生存机制，部分受到毒素-抗毒素系统(TAS)的调节。一些生物体拥有TASS的全部功能，但通过繁琐的体外实验来确定它们的活动的环境线索是困难的，特别是当有许多具有多余功能的毒素时。在这里，我们确定了BPM中103种蛋白质中的哪些与TAS毒素中发现的特征相同，并重新调整了转录数据的用途，以确定哪些蛋白质在细胞内宿主防御中发挥作用。转录反应最强的假定毒素在BPM菌株之间具有低保守性，而结构性表达的毒素具有高度保守性。对高度保守的毒素BPSS0899、BPSS1321和BPSL1494的进一步检测表明，它们是有功能的，它们的突变导致巨噬细胞内存活率降低，治疗期间体内持久性相关病理(脓肿)减少，但不影响巨噬细胞的持久性。这些发现突出了数据驱动的方法在选择推定毒素方面的实用性，并表明一些TAS在宿主生存中具有选择性作用。
Burkholderia pseudomallei (Bpm) is a bacterial pathogen that causes Melioidosis, a disease with up to 40% mortality and an infection relapse of 15–23% despite antibiotic treatment. Ineffective clearance of Bpm by antibiotics is believed to be due to persistence, a hibernation-like survival mechanism modulated, in part, by toxin–antitoxin systems (TAS). Several organisms possess a repertoire of TASs but defining environmental cues eliciting their activity is hindered by laborious in vitro experiments, especially when there are many toxins with redundant function. Here, we identified which of 103 proteins in Bpm that share features found in toxins of the TAS and repurposed transcriptional data to identify which ones play a role in surviving intracellular host defenses. Putative toxins with the strongest transcriptional response were found to have low conservation between Bpm strains, while toxins that were constitutively expressed were highly conserved. Further examination of highly conserved toxins BPSS0899, BPSS1321, and BPSL1494 showed that they were functional, and their mutation led to reduce survival within macrophages and reduced in vivo persistence-associated pathology (abscesses) during treatment, but did not affect macrophages persistence. These findings highlight the utility of a data-driven approach to select putative toxins and suggests a selective role for some TAS in host survival.
登录
查看更多内容
影响因子：
3.2
作者：
Majerczyk, Charlotte D.;Brittnacher, Mitchell J.;Greenberg, E. Peter
通讯作者：
Greenberg, E. Peter
用于选择特工Burkholderia pseudomallei和Burkholderia Mallei的符合遗传操作的等位基因交换系统。
影响因子：
3.5
作者：
Hamad, Mohamad A.;Zajdowicz, Sheryl L.;Holmes, Randall K.;Voskuil, Martin I.
通讯作者：
Voskuil, Martin I.
影响因子：
3.7
作者：
Burtnick MN;Brett PJ
通讯作者：
Brett PJ
影响因子：
5.1
作者：
Lai, Sandra;Tremblay, Julien;Deziel, Eric
通讯作者：
Deziel, Eric
鲍曼不动杆菌持久细胞的表征和转录组分析
影响因子：
2.6
作者：
Alkasir, Rashad;Ma, Yanan;Zhu, Baoli
通讯作者：
Zhu, Baoli