Functional Plasticity in the Type IV Secretion System of Helicobacter pylori

Helicobacter pylori causes clinical disease primarily in those individuals infected with a strain that carries the cytotoxin associated gene pathogenicity island (cagPAI). The cagPAI encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into epithelial cells and is required for induction of the pro-inflammatory cytokine, interleukin-8 (IL-8). CagY is an essential component of the H. pylori T4SS that has an unusual sequence structure, in which an extraordinary number of direct DNA repeats is predicted to cause rearrangements that invariably yield in-frame insertions or deletions. Here we demonstrate in murine and non-human primate models that immune-driven host selection of rearrangements in CagY is sufficient to cause gain or loss of function in the H. pylori T4SS. We propose that CagY functions as a sort of molecular switch or perhaps a rheostat that alters the function of the T4SS and “tunes” the host inflammatory response so as to maximize persistent infection.

幽门螺杆菌（Helicobacter pylori）主要在感染携带细胞毒素相关基因致病岛（cytotoxin associated gene pathogenicity island，cagPAI）菌株的个体中引发临床疾病。cagPAI编码IV型分泌系统（type IV secretion system，T4SS），该系统可将CagA癌蛋白（CagA oncoprotein）注入上皮细胞，且是诱导促炎细胞因子白细胞介素8（IL-8）表达所必需的。CagY是幽门螺杆菌T4SS的必需组分，其序列结构异常：据预测，其中存在数量极多的同向DNA重复序列，此类重复序列易引发重排，且最终始终会产生框内插入或缺失突变。本研究在小鼠与非人灵长类模型中证实，免疫驱动的宿主对CagY基因重排的选择，足以使幽门螺杆菌T4SS的功能发生获得或丧失。我们提出，CagY可作为一类分子开关或类似变阻器的调控元件，通过改变T4SS的功能并“微调”宿主炎症反应，以最大化维持持续感染的能力。