A Salmonella Typhi RNA thermosensor regulates virulence factors and innate immune evasion in response to host temperature.
A Salmonella Typhi RNA thermosensor regulates virulence factors and innate immune evasion in response to host temperature.
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伤寒沙门氏菌RNA温度传感器调节毒力因子和天然免疫逃避以响应宿主温度。
DOI：
10.1371/journal.ppat.1009345
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Monack DM
中科院分区：
文献类型：
--
作者：
Brewer SM;Twittenhoff C;Kortmann J;Brubaker SW;Honeycutt J;Massis LM;Pham THM;Narberhaus F;Monack DM
对环境信号的感知和响应对于细菌病原体成功感染并在宿主中持续存在至关重要。许多细菌病原体感觉温度作为它们已经进入新宿主的指示，并且必须改变它们的毒力因子表达以逃避免疫检测。利用二级结构预测，我们在由伤寒引起的细菌肠道沙门氏菌伤寒血清型（S.伤寒）。重要的是，tviA是关键毒力因子Vi荚膜、鞭毛蛋白和III型分泌系统-1表达的转录调节因子。通过引入点突变以改变mRNA二级结构，我们使用体外表达、结构探测和核糖体结合方法证明tviA的5' UTR含有功能性RNAT。突变抑制S.伤寒引起异常的毒力因子表达，导致感染期间增强的先天免疫应答。最后，我们证明了S.伤寒通过tviA的5' UTR中的RNAT调节毒力因子表达。我们的研究结果表明，通过响应宿主体温的RNAT依赖性调节来限制炎症对S。伤寒的“隐形”发病机制。伤寒沙门氏菌（S.伤寒（Typhi）是一种人类限制性细菌病原体，每年在全球范围内造成1100万至2100万例新的伤寒病例。急性感染时，S.伤寒逃避免疫检测并迅速全身传播，这为它赢得了“隐形”病原体的绰号。转录调节因子TviA是S.伤寒沙门氏菌是这种隐蔽表型的关键，因为它抑制了主要病原体相关分子模式的表达，并诱导了重要的毒力因子Vi荚膜，使沙门氏菌成为可能。伤寒逃避免疫检测。我们证明了S.伤寒通过位于TviA 5'非翻译区的RNA热传感器（RNAT）调节毒力因子表达以响应宿主体温，所述RNA热传感器控制TviA蛋白的产生以响应温度波动。tviA RNAT的突变扰动导致响应温度的异常毒力因子表达，并揭示了S.伤寒逃避先天免疫检测和激活。我们的工作是第一次描述了一个RNAT在一个关键的毒力因子转录调控在S。伤寒沙门氏菌中的温度敏感性，证明了温度敏感性在伤寒沙门氏菌中的重要作用。伤寒发病机制。
Sensing and responding to environmental signals is critical for bacterial pathogens to successfully infect and persist within hosts. Many bacterial pathogens sense temperature as an indication they have entered a new host and must alter their virulence factor expression to evade immune detection. Using secondary structure prediction, we identified an RNA thermosensor (RNAT) in the 5’ untranslated region (UTR) of tviA encoded by the typhoid fever-causing bacterium Salmonella enterica serovar Typhi (S. Typhi). Importantly, tviA is a transcriptional regulator of the critical virulence factors Vi capsule, flagellin, and type III secretion system-1 expression. By introducing point mutations to alter the mRNA secondary structure, we demonstrate that the 5’ UTR of tviA contains a functional RNAT using in vitro expression, structure probing, and ribosome binding methods. Mutational inhibition of the RNAT in S. Typhi causes aberrant virulence factor expression, leading to enhanced innate immune responses during infection. In conclusion, we show that S. Typhi regulates virulence factor expression through an RNAT in the 5’ UTR of tviA. Our findings demonstrate that limiting inflammation through RNAT-dependent regulation in response to host body temperature is important for S. Typhi’s “stealthy” pathogenesis. Salmonella enterica serovar Typhi (S. Typhi) is a human-restricted bacterial pathogen that causes 11–21 million new cases of typhoid fever worldwide each year. During acute infection, S. Typhi evades immune detection and rapidly spreads systemically, which has earned it the nickname of a “stealth” pathogen. The transcriptional regulator TviA is unique to S. Typhi and critical for this stealthy phenotype because it represses the expression of major pathogen-associated molecular patterns and induces the important virulence factor Vi capsule, which enable S. Typhi to evade immune detection. We show that S. Typhi regulates virulence factor expression in response to host body temperature via an RNA thermosensor (RNAT) located in the 5’ untranslated region of tviA, which controls production of TviA protein in response to temperature fluctuations. Mutational perturbation of the tviA RNAT causes aberrant virulence factor expression in response to temperature and reveals that a functional RNAT is required for S. Typhi to evade innate immune detection and activation. Our work is the first to describe an RNAT in a critical virulence factor transcriptional regulator in S. Typhi and demonstrates the important role that temperature-sensing plays in S. Typhi pathogenesis.
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DOI：
10.1093/bioinformatics/btp250
发表时间：
2009-08-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Darty K;Denise A;Ponty Y
通讯作者：
Ponty Y
影响因子：
4.1
作者：
Klinkert, Birgit;Cimdins, Annika;Narberhaus, Franz
通讯作者：
Narberhaus, Franz
影响因子：
6.7
作者：
Casadevall, Arturo
通讯作者：
Casadevall, Arturo
影响因子：
3.6
作者：
Arricau, N;Hermant, D;Popoff, MY
通讯作者：
Popoff, MY
影响因子：
64.8
作者：
Kofoed, Eric M.;Vance, Russell E.
通讯作者：
Vance, Russell E.