Stein Saskia C, Faber Eugenia, Bats Simon H, Murillo Tatiana, Speidel Yvonne, Coombs Nina, Josenhans Christine
Medizinische Hochschule Hannover, Institute for Medical Microbiology, Hannover, Germany.
German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Hannover, Germany.
PLoS Pathog. 2017 Jul 17;13(7):e1006514. doi: 10.1371/journal.ppat.1006514. eCollection 2017 Jul.
Highly virulent Helicobacter pylori cause proinflammatory signaling inducing the transcriptional activation and secretion of cytokines such as IL-8 in epithelial cells. Responsible in part for this signaling is the cag pathogenicity island (cagPAI) that codetermines the risk for pathological sequelae of an H. pylori infection such as gastric cancer. The Cag type IV secretion system (CagT4SS), encoded on the cagPAI, can translocate various molecules into cells, the effector protein CagA, peptidoglycan metabolites and DNA. Although these transported molecules are known to contribute to cellular responses to some extent, a major part of the cagPAI-induced signaling leading to IL-8 secretion remains unexplained. We report here that biosynthesis of heptose-1,7-bisphosphate (HBP), an important intermediate metabolite of LPS inner heptose core, contributes in a major way to the H. pylori cagPAI-dependent induction of proinflammatory signaling and IL-8 secretion in human epithelial cells. Mutants defective in the genes required for synthesis of HBP exhibited a more than 95% reduction of IL-8 induction and impaired CagT4SS-dependent cellular signaling. The loss of HBP biosynthesis did not abolish the ability to translocate CagA. The human cellular adaptor TIFA, which was described before to mediate HBP-dependent activity in other Gram-negative bacteria, was crucial in the cagPAI- and HBP pathway-induced responses by H. pylori in different cell types. The active metabolite was present in H. pylori lysates but not enriched in bacterial supernatants. These novel results advance our mechanistic understanding of H. pylori cagPAI-dependent signaling mediated by intracellular pattern recognition receptors. They will also allow to better dissect immunomodulatory activities by H. pylori and to improve the possibilities of intervention in cagPAI- and inflammation-driven cancerogenesis.
高毒力幽门螺杆菌可引发促炎信号，诱导上皮细胞中白细胞介素-8等细胞因子的转录激活和分泌。这种信号传导部分归因于cag致病岛（cagPAI），它共同决定了幽门螺杆菌感染（如胃癌）的病理后遗症风险。编码在cagPAI上的Cag IV型分泌系统（CagT4SS）可将各种分子转运到细胞中，包括效应蛋白CagA、肽聚糖代谢产物和DNA。虽然已知这些转运分子在一定程度上有助于细胞反应，但导致白细胞介素-8分泌的cagPAI诱导信号的主要部分仍无法解释。我们在此报告，庚糖-1,7-二磷酸（HBP）是脂多糖内庚糖核心的重要中间代谢产物，在很大程度上有助于幽门螺杆菌cagPAI依赖性促炎信号传导和人上皮细胞中白细胞介素-8的分泌。HBP合成所需基因有缺陷的突变体，其白细胞介素-8诱导减少超过95%，且CagT4SS依赖性细胞信号传导受损。HBP生物合成的缺失并未消除CagA的转运能力。人类细胞衔接蛋白TIFA，之前被描述为在其他革兰氏阴性细菌中介导HBP依赖性活性，在幽门螺杆菌在不同细胞类型中诱导的cagPAI和HBP途径反应中至关重要。活性代谢产物存在于幽门螺杆菌裂解物中，但在细菌上清液中未富集。这些新结果推进了我们对由细胞内模式识别受体介导的幽门螺杆菌cagPAI依赖性信号传导机制的理解。它们还将有助于更好地剖析幽门螺杆菌的免疫调节活性，并提高干预cagPAI和炎症驱动的癌症发生的可能性。
