Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA).
Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA).
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DOI：
10.3389/fcimb.2012.00037
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发表时间：
2012
影响因子：
5.7
通讯作者：
Blanke SR
中科院分区：
文献类型：
--
作者：
Kim IJ;Blanke SR
幽门螺杆菌持久性和疾病背后的毒力机制仍然知之甚少，部分原因是疾病风险因素是多因素且复杂的。在导致与幽门螺杆菌感染相关的累积病理生理学的细菌因素中，空泡细胞毒素（VacA）是最重要的之一。与许多幽门螺杆菌基因类似，vacA 基因表现出等位基因嵌合，人类流行病学研究表明，多个毒素等位基因家族可预测更严重的疾病。动物模型研究表明，VacA 可能通过多种方式促进发病机制。 VacA 作为一种细胞内作用蛋白外毒素。然而，VacA 并不符合目前 AB 细胞内作用细菌毒素的原型，后者通过在宿主细胞内易位的酶结构域的作用来发挥调节作用。相反，VacA 可能代表 AB 细胞内作用毒素的替代原型，该毒素通过形成离子传导的细胞内膜通道来调节细胞稳态。尽管 VacA 似乎在几种不同的膜中形成通道，但最重要的靶位点之一是线粒体内膜。 VacA 显然利用了一种不寻常的细胞内运输途径进入线粒体，在该途径中毒素被输入并使内膜去极化，从而破坏线粒体动力学和细胞能量稳态，作为参与宿主细胞内凋亡机制的机制。 VacA 对胃环境的重塑似乎是通过 IV 型效应蛋白 CagA 的作用进行微调的，CagA 在一定程度上限制了 VacA 在幽门螺杆菌定植的细胞中的细胞毒性作用。
Virulence mechanisms underlying Helicobacter pylori persistence and disease remain poorly understood, in part, because the factors underlying disease risk are multifactorial and complex. Among the bacterial factors that contribute to the cumulative pathophysiology associated with H. pylori infections, the vacuolating cytotoxin (VacA) is one of the most important. Analogous to a number of H. pylori genes, the vacA gene exhibits allelic mosaicism, and human epidemiological studies have revealed that several families of toxin alleles are predictive of more severe disease. Animal model studies suggest that VacA may contribute to pathogenesis in several ways. VacA functions as an intracellular-acting protein exotoxin. However, VacA does not fit the current prototype of AB intracellular-acting bacterial toxins, which elaborate modulatory effects through the action of an enzymatic domain translocated inside host cells. Rather, VacA may represent an alternative prototype for AB intracellular acting toxins that modulate cellular homeostasis by forming ion-conducting intracellular membrane channels. Although VacA seems to form channels in several different membranes, one of the most important target sites is the mitochondrial inner membrane. VacA apparently take advantage of an unusual intracellular trafficking pathway to mitochondria, where the toxin is imported and depolarizes the inner membrane to disrupt mitochondrial dynamics and cellular energy homeostasis as a mechanism for engaging the apoptotic machinery within host cells. VacA remodeling of the gastric environment appears to be fine-tuned through the action of the Type IV effector protein CagA which, in part, limits the cytotoxic effects of VacA in cells colonized by H. pylori.