Fig. 5: Models for TLR5-mediated and CagL-dependent H. pylori pathogenesis.

a TLR5 is not expressed in healthy gastric tissue. H. pylori infection induced the expression of TLR5 in infected gastric patients and TLR5 disappeared after eradication suggesting a tight regulation of this receptor. These data are in agreement with infection studies in WT and TLR5^−/− mice, which document that TLR5 controls immune responses and colonization by H. pylori. TLR5 recognition of H. pylori occurs through the T4SS pilus protein CagL having a D1 mimetic motif, while recognition of flagellin is avoided. In addition, CagL-mediated TLR5 activation up-regulated the expression of several chemokines and cytokines, as well as its receptors. Various immune cell attracting chemokines such as CXCL1, CXCL3, CCL2, CXCL10, CCL20 and cytokines TNF, IL-32 and IL-17F were increased both by TLR5-dependent and -independent signaling pathways as indicated. Moreover, the combined expression of CCL20, TNF and TNF receptor (TNFR) imply the induction of mucosal lymphoid tissue formation through TLR5-dependent signaling. Infected gastric biopsies from patients exhibit an increased expression of TLR5 on plasma cells in the gastric mucosa. This raises the possibility of CagL-TLR5 dependent IgA production in mucosal lymphoid tissues and secretion into the gastric lumen to control the H. pylori infection. The various signaling-engaged protein classes are highlighted with different colors as outlined at the bottom. b H. pylori expresses an unresponsive flagellin (“OFF” status) and instead expresses the T4SS-pilus surface protein CagL, which can trigger TLR5 activation when T4SS pili are expressed (“ON” status). c However, T4SS pilus functions can be turned on and off through recombination in T4SS proteins⁸. This shift provides H. pylori with the unique ability to avoid permanent TLR5 activation by hiding CagL in the T4SS “OFF” status. We propose that, by engaging TLR5, H. pylori may be able to control the host inflammatory response and its own colonization.