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

Author

Listed:
  • 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
    The Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania)

  • 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)

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.

Suggested Citation

  • 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. Murp, 2020. "African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14151-9
    DOI: 10.1038/s41467-019-14151-9
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