Clinical isolates of the opportunistic pathogen Pseudomonas aeruginosa from patients with cystic fibrosis (CF) frequently contain mutations in the gene encoding an elongation factor, FusA1. Recent work has shown that fusA1 mutants often display elevated aminoglycoside resistance due to increased expression of the efflux pump, MexXY. However, we wondered whether these mutants might also be affected in other virulence-associated phenotypes. Here, we isolated a spontaneous gentamicin-resistant fusA1 mutant (FusA1P443L) in which mexXY expression was increased. Proteomic and transcriptomic analyses revealed that the fusA1 mutant also exhibited discrete changes in the expression of key pathogenicity-associated genes. Most notably, the fusA1 mutant displayed greatly increased expression of the Type III secretion system (T3SS), widely considered to be the most potent virulence factor in the P. aeruginosa arsenal, and also elevated expression of the Type VI (T6) secretion machinery. This was unexpected because expression of the T3SS is usually reciprocally coordinated with T6 secretion system expression. The fusA1 mutant also displayed elevated exopolysaccharide production, dysregulated siderophore production, elevated ribosome synthesis, and transcriptomic signatures indicative of translational stress. Each of these phenotypes (and almost all of the transcriptomic and proteomic changes associated with the fusA1 mutation) were restored to levels comparable with that in the progenitor strain by expression of the WT fusA1 gene in trans, indicating that the mutant gene is recessive. Our data show that in addition to elevating antibiotic resistance through mexXY expression (and also additional contributory resistance mechanisms), mutations in fusA1 can lead to highly selective dysregulation of virulence gene expression.

中文翻译：

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通过延伸因子 fusA1 的单核苷酸多态性对铜绿假单胞菌的毒力和抗生素耐药性进行全局重编程。

来自囊性纤维化 (CF) 患者的机会性病原体铜绿假单胞菌的临床分离物通常在编码伸长因子 FusA1 的基因中包含突变。最近的工作表明，由于外排泵 MexXY 的表达增加，fusA1 突变体通常表现出较高的氨基糖苷类耐药性。然而，我们想知道这些突变体是否也可能受到其他毒力相关表型的影响。在这里，我们分离了自发的庆大霉素抗性 fusA1 突变体 (FusA1P443L)，其中 mexXY 表达增加。蛋白质组学和转录组学分析表明，fusA1 突变体还表现出关键致病性相关基因表达的离散变化。最值得注意的是，fusA1 突变体显示出大大增加的 III 型分泌系统（T3SS）的表达，被广泛认为是铜绿假单胞菌库中最有效的毒力因子，并且还提高了 VI 型 (T6) 分泌机制的表达。这是出乎意料的，因为 T3SS 的表达通常与 T6 分泌系统表达相互协调。fusA1 突变体还表现出胞外多糖产生增加、铁载体产生失调、核糖体合成增加以及表明翻译压力的转录组学特征。这些表型中的每一个（以及几乎所有与 fusA1 突变相关的转录组学和蛋白质组学变化）都通过反式表达 WT fusA1 基因恢复到与祖株相当的水平，表明突变基因是隐性的。