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TARGETED IN VIVO COMPETITION AMONG CO-INFECTING HELICOBACTER PYLORI STRAINS INCREASES CAGA-DEPENDENT INFLAMMATION, INJURY, AND CARCINOGENESIS WITHIN THE CONTEXT OF IRON DEFICIENCY

Date
May 18, 2024

Helicobacter pylori is the strongest known risk factor for gastric cancer, and pathologic outcomes are mediated via complex interactions among H. pylori virulence factors, host immune responses, and the exposome. One virulence factor that augments cancer risk is the cag type IV secretion system (T4SS), which translocates the bacterial oncoprotein CagA into host cells. In conjunction with bacterial factors, environmental conditions such as iron deficiency also influence disease. We previously demonstrated that iron deficiency augments H. pylori-induced gastric carcinogenesis via increased assembly and function of the T4SS. However, our groups have demonstrated that CagA also modulates epithelial cell iron homeostasis and fundamental microbial metabolic functions. We hypothesized that H. pylori cag+ strains harbor a competitive advantage over cagA- strains, particularly under conditions of iron deficiency. To test this hypothesis, competition experiments were performed in which Mongolian gerbils were maintained on iron-replete or iron-depleted diets and then challenged with (A) 2x109 CFU of the wild-type cag+ H. pylori strain 7.13, (B) 2x109 CFU of a 7.13 cagA- isogenic mutant, or (C) an equal mixture of 1x109 CFU of wild-type strain 7.13 and 1x109 CFU of a 7.13 cagA- isogenic mutant. As previously reported following an eight-week infection, wild-type H. pylori exhibited similar colonization levels under iron-replete vs. iron-depleted conditions. However, our new results demonstrate that the cagA- isogenic mutant exhibited a >20-fold reduction (P<0.001) in colonization levels under iron-depleted compared to iron-replete conditions, indicating that CagA provides a selective advantage in vivo during iron deficiency. In competition experiments, wild-type H. pylori outcompeted the cagA- mutant under both iron-replete and iron-depleted conditions. However, despite receiving only half the bacterial inoculum, gerbils challenged with wild-type H. pylori in competition not only developed similar levels of inflammation but also a marked increase in cancer incidence (75% vs. 50%) within the context of iron deficiency, compared to iron-deficient gerbils infected with wild-type H. pylori alone. When inflammation was normalized to inoculum levels, wild-type H. pylori during competition induced significantly higher levels of gastric inflammation compared to wild-type H. pylori alone under conditions of iron deficiency (19.3 vs. 9.5, mean inflammation score, P<0.0001). Collectively, these data suggest that bacterial competition may enhance H. pylori virulence leading to more severe gastric injury and disease. Implications from this work suggest that patients harboring multiple H. pylori strains may harbor a greater risk for adverse disease outcomes due to amplification of microbial virulence potential among competing strains.

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Speaker Image for Jennifer Noto
Vanderbilt University Medical Center

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