African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin

Kumar Sachin Singh, Julia I-Ju Leu, Thibaut Barnoud, Prashanthi Vonteddu, Keerthana Gnanapradeepan, Cindy Lin, Qin Liu, James C. Barton, Andrew V. Kossenkov, Donna L. George (), Maureen E. Murphy () and Farokh Dotiwala ()
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Kumar Sachin Singh: The Wistar Institute
Julia I-Ju Leu: The Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
Thibaut Barnoud: The Wistar Institute
Prashanthi Vonteddu: The Wistar Institute
Keerthana Gnanapradeepan: The Wistar Institute
Cindy Lin: The Wistar Institute
Qin Liu: The Wistar Institute
James C. Barton: University of Alabama at Birmingham
Andrew V. Kossenkov: The Wistar Institute
Donna L. George: The Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
Maureen E. Murphy: The Wistar Institute
Farokh Dotiwala: The Wistar Institute

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14151-9

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