• T4SS-dependent TLR5 activation by Helicobacter pylori infection.

      Pachathundikandi, Suneesh Kumar; Tegtmeyer, Nicole; Arnold, Isabelle Catherine; Lind, Judith; Neddermann, Matthias; Falkeis-Veits, Christina; Chattopadhyay, Sujay; Brönstrup, Mark; Tegge, Werner; Hong, Minsun; et al. (Nature publishing group, 2019-12-16)
      Toll-like receptor TLR5 recognizes a conserved domain, termed D1, that is present in flagellins of several pathogenic bacteria but not in Helicobacter pylori. Highly virulent H. pylori strains possess a type IV secretion system (T4SS) for delivery of virulence factors into gastric epithelial cells. Here, we show that one of the H. pylori T4SS components, protein CagL, can act as a flagellin-independent TLR5 activator. CagL contains a D1-like motif that mediates adherence to TLR5+ epithelial cells, TLR5 activation, and downstream signaling in vitro. TLR5 expression is associated with H. pylori infection and gastric lesions in human biopsies. Using Tlr5-knockout and wild-type mice, we show that TLR5 is important for efficient control of H. pylori infection. Our results indicate that CagL, by activating TLR5, may modulate immune responses to H. pylori.
    • Toll-like Receptor 5 Activation by the CagY Repeat Domains of Helicobacter pylori.

      Tegtmeyer, Nicole; Neddermann, Matthias; Lind, Judith; Pachathundikandi, Suneesh Kumar; Sharafutdinov, Irshad; Gutiérrez-Escobar, Andrés Julián; Brönstrup, Mark; Tegge, Werner; Hong, Minsun; Rohde, Manfred; et al. (Cell Press, 2020-11-15)
      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.