Toxin-antitoxin systems are found in many bacterial chromosomes and plasmids with roles ranging from plasmid stabilization to biofilm formation and persistence. In these systems, the expression/activity of the toxin is counteracted by an antitoxin, which in type I systems is an antisense-RNA. While the regulatory mechanisms of these systems are mostly well-defined, the toxins biological activity and expression conditions are less understood. Here, these questions were investigated for a type I toxin-antitoxin system (AapA1-IsoA1) expressed from the chromosome of the human pathogen Helicobacter pylori. We show that expression of the AapA1 toxin in H. pylori causes growth arrest associated with rapid morphological transformation from spiral-shaped bacteria to round coccoid cells. Coccoids are observed in patients and during in vitro growth as a response to different stress conditions. The AapA1 toxin, first molecular effector of coccoids to be identified, targets H. pylori inner membrane without disrupting it, as visualized by Cryo-EM. The peptidoglycan composition of coccoids is modified with respect to spiral bacteria. No major changes in membrane potential or ATP concentration result from AapA1 expression, suggesting coccoid viability. Single-cell live microscopy tracking the shape conversion suggests a possible association of this process with cell elongation/division interference. Oxidative stress induces coccoid formation and is associated with repression of the antitoxin promoter and enhanced processing of its transcript, leading to an imbalance in favor of AapA1 toxin expression. Our data support the hypothesis of viable coccoids with characteristics of dormant bacteria that might be important in H. pylori infections refractory to treatment.

中文翻译：

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I型毒素-抗毒素系统的肽诱导幽门螺杆菌从螺旋形转变为类球体

在许多细菌染色体和质粒中发现了毒素-抗毒素系统，其作用范围从质粒稳定到生物膜形成和持久性。在这些系统中，毒素的表达/活性被抗毒素抵消，抗毒素在I型系统中是反义RNA。虽然这些系统的调节机制大多是明确的，但对毒素的生物学活性和表达条件却知之甚少。在这里，针对从人类病原体幽门螺杆菌的染色体表达的I型毒素-抗毒素系统（AapA1-IsoA1）研究了这些问题。我们显示在幽门螺杆菌中的AapA1毒素的表达引起与从螺旋形细菌到圆形球状细胞的快速形态转化有关的生长停滞。在患者体内和体外生长过程中观察到了球状体，作为对不同压力条件的反应。正如Cryo-EM所观察到的，AapA1毒素是待鉴定的类球体的第一个分子效应子，它靶向幽门螺杆菌内膜而不会破坏它。球形蛋白的肽聚糖组成相对于螺旋细菌被修饰。AapA1的表达不会引起膜电位或ATP浓度的重大变化，这表明球菌的生存力。跟踪形状转换的单细胞活显微镜检查表明该过程可能与细胞伸长/分裂干扰有关。氧化应激诱导类球体形成，并与抗毒素启动子的抑制和其转录物的增强处理有关，从而导致不平衡的AapA1毒素表达。