Role of the p53 P47S mutation in influencing prevalence and immune response to H. pylori

Wistar Institute, Philadelphia PA

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Abstract

We discovered that a human TP53 gene variant at amino acid 47 codes for a “hypomorphic” p53 protein. This hypomorph p53 variant (P47S) retains most but not all of its functions and has been linked to changes in innate and adaptive immunity. Macrophages containing the P47S variant are defective in ferroptosis, M2 polarized, and show more productive infections by H. pylori (Hp) and other bacteria. Macrophage adaptive response is essential for eliminating Hp infection and is suppressed in chronic infections that lead to gastritis. Unbiased WT and P47S macrophage proteomics revealed marked differences in Liver X Receptor activation, arginase II activity, inflammation, iron transport, and antibacterial defense machinery which regulate immune response and directly affect outcomes of bacterial infections. Although p53 is known to regulate immune response, we are the first to discover the exact genetic variant causing the effect on innate immunity. In this project, we aim to reduce exacerbated Hp infection damage associated with the P47S SNP by in-depth mechanistic and therapeutic study. Our human studies will give translational relevance to this project. We will test ~500 Hp seropositive individuals for the prevalence of P47S and other SNPs. Then we will focus on improving macrophage response, Hp clearance, and reduce chronic gastric dysplasia in P47S mice using Liver X Receptor (LXR) agonists. Moreover, we will generate a genome-wide map of macrophage binding of LXR to ‘fine tune’ its activity on macrophage activation and eliminate undesired effect of hepatic steatosis. Since Hp is found both extracellularly and within macrophages, specific depletion of immune cells will be used to distinguish the role of macrophages from other tissue environment in Hp pathogenesis. These studies will be validated by bone marrow swaps between WT and P47S mice. We will prioritize and test pathways associated with LXR such as arginase pathway (Arg2, Slc7a2), iron transport (Tfrc, Slc40a1, Fth1) and innate immune proteins (TLR3 and TLR7) as novel therapeutic targets. Lastly, we will test macrophage regulatory factors (NOTCH1 and mTOR), energy metabolism (switching from ox-phos to glycolysis by Metformin) and polyamine pathway (DFMO-polyamine synthesis inhibitor) in fine tuning LXR agonist induced reversal of anti-inflammatory polarization in P47S mice, clearance of Hp infection, and reduction of gastric dysplasia. This proposal will provide translational relevance by associating the P47S SNP to increased Hp prevalence and pathogenesis while providing several therapeutic avenues to improve clearance of Hp infection and gastritis.