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

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.

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For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors/reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Research guidelines for submitting code & software for further information. Sample size calculated based on statistics of previous bacteria infection studies. WT and S47, male mice at 8 weeks age were randomly assigned to the experimental groups. A group size of n = 10 mice (unless otherwise mentioned) provided 90% power to detect 2 to 10-fold increase in Hp infection in S47 mice. DNA of African Americans with elevated saturated serum transferrin levels, for human studies was obtained randomized from the HEIRS study.

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DNA samples from 479 African Americans with elevated transferrin saturation and serum ferritin were compared with (OR 1.68 (95% CI 1.07-2.65) p=0.023) Male mice were used for all studies once data revealed only modest differences in iron levels and anti-inflammatory polarization between WT and S47 female mice. Controls and experimental groups were age and genotype-matched non-littermates.
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nature research | reporting summary
October 2018

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Wild-type (WT) and S47 humanized TP53 knock-in (Hupki) mice were generated by Dr. Maureen Murphy (The Wistar Institute, Philadelphia, PA). All mice were backcrossed to C57bBl/6 for >10 generations, and sibling littermates were used for majority of the analyses. Mice were housed in plastic cages with ad libitum diet and maintained with a 12-hr light/12-hr dark cycle at 22°C. Male mice were used for all studies once data revealed modest differences in iron levels between WT and S47 female mice. Controls and experimental groups were age and genotype-matched non-littermates.
no wild animals involved no field samples collected All protocols were approved by The Wistar Institute and the Perelman School of Medicine at the University of Pennsylvania, Institutional Animal Care and Use Committee (IACUC) We analyzed the TP53 SNP rs1800371 in 479 African American samples, both men and women who were HEIRS Study participants $25 years of age. Samples were obtained from participants after they provided informed consent. All participants had elevated transferrin saturation (>50%); in approximately one quarter of the cases, participants also had serum ferritin values >300 µg/mL. DNA samples or buffy coat punches were obtained from the HEIRS Study, part of the BioLINCC repository of the National Heart Lung and Blood Institute.
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