Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans.
Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans.
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DOI：
10.1053/j.gastro.2012.01.043
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发表时间：
2012-05
期刊：
影响因子：
29.4
通讯作者：
Jones NL
中科院分区：
文献类型：
--
作者：
Raju D;Hussey S;Ang M;Terebiznik MR;Sibony M;Galindo-Mata E;Gupta V;Blanke SR;Delgado A;Romero-Gallo J;Ramjeet MS;Mascarenhas H;Peek RM;Correa P;Streutker C;Hold G;Kunstmann E;Yoshimori T;Silverberg MS;Girardin SE;Philpott DJ;El Omar E;Jones NL
幽门螺杆菌毒素空泡细胞毒素（VacA）促进胃定植，其存在（VacA+）与更严重的疾病相关。VacA导致感染的确切机制尚不清楚。我们以前发现，有限暴露于VacA诱导胃细胞的自噬，从而消除毒素;我们研究了自噬是否作为抵抗幽门螺杆菌感染的防御机制。我们研究了VacA对人胃上皮细胞（AGS）和小鼠原代胃细胞自噬的影响。p62的表达，自噬的标志物，也进行了评估，在胃组织中的患者感染的致病性（VacA+）或非致病性菌株。我们分析了VacA对外周血单核细胞自噬的影响，这些单核细胞来自具有不同基因型ATG 16 L1（调节自噬）的受试者。我们在感染和未感染受试者的两个队列中对ATG 16 L1进行基因分型。AGS和小鼠胃细胞长时间暴露于VacA破坏了对毒素的自噬诱导，因为细胞自噬体中缺乏组织蛋白酶D。自噬的丧失导致p62和活性氧的积累。来自VacA+感染患者的胃活检样本，而非非幽门螺杆菌的非致突变菌株，p62水平升高。与来自没有这些多态性的个体的细胞相比，从具有增加克罗恩病易感性的ATG 16 L1多态性的个体分离的外周血单核细胞减少了响应于VacA+的自噬诱导。在2个单独的队列中，存在ATG 16 L1克罗恩病风险变异体增加了幽门螺杆菌感染的易感性。自噬可以防止幽门螺杆菌感染;毒素VacA破坏自噬以促进感染，这可能导致炎症和最终的致癌作用。
The Helicobacter pylori toxin vacuolating cytotoxin (VacA) promotes gastric colonization and its presence (VacA+) is associated with more-severe disease. The exact mechanisms by which VacA contributes to infection are unclear. We previously found that limited exposure to VacA induces autophagy of gastric cells, which eliminates the toxin; we investigated whether autophagy serves as a defense mechanism against H pylori infection. We investigated the effect of VacA on autophagy in human gastric epithelial cells (AGS) and primary gastric cells from mice. Expression of p62, a marker of autophagy, was also assessed in gastric tissues from patients infected with toxigenic (VacA+) or nontoxigenic strains. We analyzed the effect of VacA on autophagy in peripheral blood monocytes obtained from subjects with different genotypes of ATG16L1, which regulates autophagy. We performed genotyping for ATG16L1 in two cohorts of infected and uninfected subjects. Prolonged exposure of AGS and mouse gastric cells to VacA disrupted induction of autophagy in response to the toxin, because the cells lacked cathepsin-D in autophagosomes. Loss of autophagy resulted in the accumulation of p62 and reactive oxygen species. Gastric biopsies samples from patients infected with VacA+, but not nontoxigenic strains of H pylori, had increased levels of p62. Peripheral blood monocytes isolated from individuals with polymorphisms in ATG16L1 that increase susceptibility to Crohn's disease had reduced induction of autophagy in response to VacA+ compared to cells from individuals that did not have these polymorphisms. The presence of the ATG16L1 Crohn’s disease risk variant increased susceptibility to H pylori infection in 2 separate cohorts. Autophagy protects against infection with H pylori; the toxin VacA disrupts autophagy to promote infection, which could contribute to inflammation and eventual carcinogenesis.
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