Abstract
Helicobacter pylori (Hp) secrete VacA, a diffusible pore-forming exotoxin that is epidemiologically linked to gastric disease in humans. In vitro studies indicate that VacA modulates gastric epithelial and immune cells, but the in vivo contributions of VacA as an important determinant of Hp colonization and chronic infection remain poorly understood. To identify perturbations in the stomachs of C57BL/6 or BALB/C mice that result specifically from extended VacA exposure, we evaluated the efficacy of administering purified toxin using automated infusion via surgically-implanted, intragastric catheters. At 3 and 30 days of interrupted infusion, VacA was detected in association with gastric glands. In contrast to previously-reported tissue damage resulting from short term exposure to Hp extracts administered by oral gavage, extended infusion of VacA did not damage stomach, esophageal, intestinal, or liver tissue. However, several alterations previously reported during Hp infection were detected in animals infused with VacA, including reduction of the gastric mucus layer, and increased vacuolation of parietal cells. VacA infusion invoked an immune response, as indicated by the detection of circulating VacA antibodies. These foundational studies support the use of VacA infusion for identifying gastric alterations that are unambiguously attributable to long-term exposure to toxin.
Highlights
Helicobacter pylori (Hp) chronically infects half the world’s population, and is a major risk factor for the development of gastric ulcer disease and cancer[1,2,3]
Because subjects are often unaware of their infection status until the emergence of clinical disease, relatively little is known about the natural history of Hp infection over extended periods of time, including the contributions of individual virulence factors to bacterial persistence and disease progression
The in vivo consequences of long-term exposure to vacuolating cytotoxin (VacA), which is secreted by Hp into the extracellular environment as a diffusible exotoxin during infection, are poorly understood
Summary
Helicobacter pylori (Hp) chronically infects half the world’s population, and is a major risk factor for the development of gastric ulcer disease and cancer[1,2,3]. Cell culture models have provided elegant insights into the consequences of VacA intoxication of epithelial cells, which include mitochondrial dysfunction and disruption of metabolic homeostasis[20,21], the biogenesis of large intracellular vacuoles[22,23,24], and, at higher concentrations, death by several distinct mechanisms[25,26,27,28,29,30,31,32,33,34,35] Understanding these in vitro observations in the context of chronic Hp infection has been challenging, in part, because the biodistribution of VacA in the stomachs of Hp-infected individuals is poorly understood. With the goal of overcoming this limitation, we assessed the efficacy of intragastric infusion to administer VacA, for extended and uninterrupted periods of time, directly into the stomach lumen of C57BL/6 and BALB/C mice
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