Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
Toxins (Basel). 2018 May 4;10(5):185. doi: 10.3390/toxins10050185.
The effector protein Exotoxin Y (ExoY) produced by is injected via the type III secretion system (T3SS) into host cells. ExoY acts as nucleotidyl cyclase promoting the intracellular accumulation of cyclic nucleotides. To what extent nucleotidyl cyclase activity contributes to the pathogenicity of ExoY and which mechanisms participate in the manifestation of lung infection is still unclear. Here, we used an acute airway infection model in mice to address the role of ExoY in lung infection. In infected lungs, a dose-dependent phenotype of infection with bacteria-expressing ExoY was mirrored by haemorrhage, formation of interstitial oedema in alveolar septa, and infiltration of the perivascular space with erythrocytes and neutrophilic granulocytes. Analyses of the infection process on the cellular and organismal level comparing infections with mutants expressing either nucleotidyl cyclase-active or -inactive ExoY revealed differential cytokine secretion, increased prevalence of apoptosis, and a break of lung barrier integrity in mice infected with cyclase-active ExoY. Notably, of all measured cyclic nucleotides, only the increase of cyclic UMP in infected mouse lungs coincides temporally with the observed early pathologic changes. In summary, our results suggest that the nucleotidyl cyclase activity of ExoY can contribute to acute pathogenicity.
由 产生的效应蛋白 Exotoxin Y（ExoY）通过 III 型分泌系统（T3SS）注入宿主细胞。ExoY 作为核苷酸环化酶，促进细胞内环核苷酸的积累。核苷酸环化酶活性在多大程度上促进 ExoY 的致病性，以及哪些机制参与肺感染的表现，目前仍不清楚。在这里，我们使用小鼠急性气道感染模型来研究 ExoY 在肺感染中的作用。在感染的肺部，表达 ExoY 的细菌感染的剂量依赖性表型反映在出血、肺泡隔间质水肿的形成以及血管周围空间中红细胞和嗜中性粒细胞的浸润。在比较表达具有核苷酸环化酶活性或非活性 ExoY 的 突变体的感染时，对细胞和机体水平的感染过程进行分析，结果显示细胞因子分泌增加、细胞凋亡增加以及感染具有环化酶活性 ExoY 的小鼠的肺屏障完整性被破坏。值得注意的是，在所测量的所有环核苷酸中，只有感染小鼠肺部环 UMP 的增加与观察到的早期病理变化在时间上一致。总之，我们的结果表明 ExoY 的核苷酸环化酶活性可能有助于 的急性致病性。
