Host and microbial factors influence helicobacter pylori localization and disease progression [electronic resource]

Helicobacter pylori is a human specific pathogen that chronically infects the stomachs of over half of the world's population. Infection with H. pylori strains expressing the virulence factor, CagA, greatly increases the risk of developing gastric cancer, although only a subset of infected individuals develop severe disease. It is therefore important to define factors that contribute to disease progression in the context of H. pylori infection. This body of work began with developing a CagA+ mouse model in which both H. pylori and mouse genetics can be used to study disease development. Using this system, we have identified three novel factors that influence disease progression. Two months after oral infection, mice develop precancerous lesions such as mucous metaplasia. However, animals infected as neonates are protected from developing lesions compared to mice infected as adults, suggesting that the age of infection is an important risk factor for disease development. Using 3D confocal microscopy, we discovered that H. pylori preferentially colonizes gastric glands in the antrum of the stomach. A chemotaxis mutant that is unable to properly sense and respond to its environment can colonize the surface of the stomach but fails to colonize the mid-gastric glands. Development of pathology is reduced in animals infected with the chemotaxis mutant, indicating that bacterial factors that affect localization of H. pylori within the glands is important for disease progression. Surprisingly, we discovered that the severity of pathology in genetically identical C57BL/6 mice from two different vendors is dramatically different. Mice from one vendor develop an antrum-dominant infection and inflammation, but fail to develop precancerous lesions. Mice from the second vendor develop precancerous lesions, and the infection and inflammatory response are distributed throughout the stomach. Our findings align with disease progression observed in human infection with H. pylori, in which an antrum-dominant gastritis is protective against cancerous lesions and pan-gastritis is associated with gastric cancer development. We suspected that the gut microbiota is an environmental factor that influences differences in H. pylori localization and host pathology. By co-housing animals from the two vendors or perturbing the flora with antibiotics prior to infection with H. pylori, we found that both bacterial localization and pathology could be shifted to the corpus in the animals from the first vendor, suggesting that the microbiota may influence H. pylori localization and disease progression. Since mice from second vendor had a dominant phenotype in the co-housing experiments, we compared the gut microbiota composition of the animals by sequencing fecal samples obtained before and after co-housing. The microbiota of the animals from the two vendors were different prior to co-housing, but after co-housing, the microbiota of both groups was similar to the animals from the second vendor. These findings support the observation that mice from the first vendor phenocopy mice from the second vendor after co-housing. We are currently identifying specific components of the microbiota that may be responsible for shifting the phenotype. Analysis of differences in the immune response of animals from the two vendors suggest that the microbiota may shift the immune balance in response to H. pylori infection and lead to differential disease outcomes. Using our mouse model of infection, we have identified novel host, bacterial and environmental factors that contribute to H. pylori-induced disease progression.

Keywords: Microbiology and Immunology
Advisor: Amieva Manuel primary advisor. Thesis advisor
Falkow Stanley advisor. Thesis advisor
Kuo Calvin Jay advisor. Thesis advisor
Singh Upinder (Physician)