Helicobacter pylori (Hp) is an important human pathogen associated with gastric inflammation and neoplasia. It is commonly believed that this bacterium avoids major immune recognition by Toll-like receptors (TLRs) because of low intrinsic activity of its flagellin and lipopolysaccharides (LPS). In particular, TLR5 specifically detects flagellins in various bacterial pathogens, while Hp evolved mutations in flagellin to evade detection through TLR5. Cancerogenic Hp strains encode a type IV secretion system (T4SS). The T4SS core component and pilus-associated protein CagY, a large VirB10 ortholog, drives effector molecule translocation. Here, we identify CagY as a flagellin-independent TLR5 agonist. We detect five TLR5 interaction sites, promoting binding of CagY-positive Hp to TLR5-expressing cells, TLR5 stimulation, and intracellular signal transduction. Consequently, CagY constitutes a remarkable VirB10 member detected by TLR5, driving crucial innate immune responses by this human pathogen.

幽门螺杆菌（Hp）是一种重要的人类病原体，与胃部炎症和瘤形成相关。通常认为，该细菌由于鞭毛蛋白和脂多糖（LPS）的固有活性低，避免了Toll样受体（TLR）的主要免疫识别。特别地，TLR5特异性检测各种细菌病原体中的鞭毛蛋白，而Hp在鞭毛蛋白中进化出突变以逃避通过TLR5的检测。致癌的Hp菌株编码IV型分泌系统（T4SS）。T4SS核心组件和菌毛相关蛋白CagY（大型VirB10直系同源基因）驱动效应子分子移位。在这里，我们确定CagY为鞭毛独立的TLR5激动剂。我们检测到五个TLR5相互作用位点，促进CagY阳性Hp与TLR5表达细胞的结合，TLR5刺激和细胞内信号转导。因此，CagY构成了由TLR5检测到的非凡的VirB10成员，从而驱动了这种人类病原体的关键先天免疫应答。