1. African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin.
- Author
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Singh KS, Leu JI, Barnoud T, Vonteddu P, Gnanapradeepan K, Lin C, Liu Q, Barton JC, Kossenkov AV, George DL, Murphy ME, and Dotiwala F
- Subjects
- Africa South of the Sahara, Black or African American genetics, Animals, Bacterial Infections etiology, Bacterial Infections genetics, Bacterial Infections metabolism, Ferritins blood, Ferroptosis drug effects, Ferroptosis genetics, Ferroptosis physiology, Genetic Variation, Hemeproteins toxicity, Humans, Listeriosis etiology, Liver X Receptors agonists, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Malaria genetics, Malaria metabolism, Mice, Mice, Transgenic, Transferrin metabolism, Iron metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07-2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa.
- Published
- 2020
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