The S47 p53 hypomorph allele is associated with attenuated innate immunity leading to suboptimal control of Helicobacter pylori with broad implications for human disease 4137

Abstract Description H. pylori is a gram-negative bacterium colonizing almost half the global population. P53 is a tumor suppressor gene frequently mutated in cancer, and the P47S hypomorph variant of p53 is predominantly found in African Americans. We have previously shown that in a human p53 knock-in mouse model, the S47 p53 hypomorph allele is associated with attenuated adaptive and innate immunity. We propose this may affect the ability of S47 p53 bearing humans to clear bacterial infections and contribute to elevated incidence of gastric cancer in African Americans. To test this, we developed a mouse model of acute and chronic H. pylori infection in S47 mice to evaluate H. pylori mediated pathology and the associated innate immune response. S47 mice were highly susceptible to H. pylori infection, with male and female mice exhibiting significantly higher colonization than WT in acute infection. Bacterial loads normalized between genotypes during chronic infection, but S47 mice consistently demonstrated fewer infiltrating macrophages, suggesting a deficit in myeloid trafficking and possibly function. Indeed, we demonstrate that S47 derived macrophages secrete fewer inflammatory cytokines and exhibit a tolerogenic phenotype. Understanding the mechanisms by which less functional p53 variants, typically affecting cancer incidence, strongly affects innate immunity will have implications for understanding increased disease susceptibility in humans harboring this S47 allele. Funding Sources Supported by R01 DK124385 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)