Helicobacter pylori γ-glutamyltransferase relates to proteomic adaptions important for gastric colonization
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Helicobacter pylori γ-glutamyltransferase (gGT) is a virulence factor that promotes bacterial colonization and immune tolerance. Although some studies addressed potential functional mechanisms, the supportive role of gGT for in-vivo colonization remains unclear. Additionally, it is unknown how different gGT expression levels may lead to compensatory mechanisms ensuring infection and persistence. Hence, it is crucial to unravel the in-vivo function of gGT. We assessed acid survival under conditions mimicking the human gastric fluid and elevated the pH in the murine stomach prior to H. pylori infection to link gGT-mediated acid resistance to colonization. By comparing proteomes of gGT-proficient and -deficient isolates before and after infecting mice, we investigated proteomic adaptations of gGT-deficient bacteria during infection. Our data indicate that gGT is crucial to sustain urease activity in acidic environments, thereby supporting survival and successful colonization. Absence of gGT triggers expression of proteins involved in the nitrogen and iron metabolism and boosts the expression of adhesins and flagellar proteins during infection, resulting in increased motility and adhesion capacity. In summary, gGT-dependent mechanisms confer a growth advantage to the bacterium in the gastric environment, which renders gGT a valuable target for the development of new treatments against H. pylori infection.
Author Summary
H. pylori γ-glutamyltransferase (gGT) is a virulence factor that strongly supports bacterial colonization. Despite considerable research on the function of gGT, the exact role of this enzyme in ensuring in-vivo infection remained elusive. We developed a novel system that allowed us to selectively inhibit gGT-activity and used this model to assess the function of gGT in the gastric environment. We found that gGT sustains urease activity in acidic environments thereby facilitating survival and effective colonization. In addition, we identified several compensatory mechanisms triggered by the loss of gGT which ensure colonization and persistence. These mechanisms included increased flagellar motility, adhesion capacity and expression of proteins involved in the nitrogen and iron metabolism. These findings unraveled novel functional roles of gGT important for bacterial colonization and thereby confirmed gGT as a promising target for novel treatments against H. pylori infection. By comprehensively addressing the compensatory mechanisms resulting from the loss of gGT-activity, the success of such new treatments can be improved.
