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

Pubmed ID: 31980600

Pubmed Central ID: PMC6981190

Journal: Nature communications

Publication Date: Jan. 24, 2020

Affiliation: Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, 19104, USA. fdotiwala@wistar.org.

MeSH Terms: Humans, Animals, Mice, Iron, Genetic Variation, Mice, Transgenic, Transferrin, Ferritins, Africa South of the Sahara, Bacterial Infections, Ferroptosis, Hemeproteins, Listeriosis, Liver X Receptors, Macrophages, Malaria, Tumor Suppressor Protein p53, Black or African American

Grants: P01 CA114046, F32 CA220972, P01 CA098101, P01 DK049210, P30 DK050306, P30 CA010815, R01 CA102184, R01 CA201430, R21 HL144991, R01 CA139319, R50 CA211199, R50 CA221838

Authors: Barton JC, Singh KS, Leu JI, Barnoud T, Vonteddu P, Gnanapradeepan K, Lin C, Liu Q, Kossenkov AV, George DL, Murphy ME, Dotiwala F

Cite As: Singh KS, Leu JI, Barnoud T, Vonteddu P, Gnanapradeepan K, Lin C, Liu Q, Barton JC, Kossenkov AV, George DL, Murphy ME, Dotiwala F. African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin. Nat Commun 2020 Jan 24;11(1):473.

Studies:

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.