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

Nat Commun. 2020 Jan 24;11(1):473. doi: 10.1038/s41467-019-14151-9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Africa South of the Sahara
  • Animals
  • Bacterial Infections / etiology
  • Bacterial Infections / genetics
  • Bacterial Infections / metabolism
  • Black or African American / genetics
  • Ferritins / blood
  • Ferroptosis / drug effects
  • Ferroptosis / genetics
  • Ferroptosis / physiology
  • Genetic Variation
  • Hemeproteins / toxicity
  • Humans
  • Iron / metabolism*
  • Listeriosis / etiology
  • Liver X Receptors / agonists
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Malaria / genetics
  • Malaria / metabolism
  • Mice
  • Mice, Transgenic
  • Transferrin / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Hemeproteins
  • Liver X Receptors
  • TP53 protein, human
  • Transferrin
  • Tumor Suppressor Protein p53
  • hemozoin
  • Ferritins
  • Iron