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

Area of Science:

• Immunology
• Genetics
• Cell Biology

Background:

• A TP53 variant (P47S) prevalent in individuals of African descent is linked to increased cancer risk via defective ferroptosis.
• Ferroptosis is a regulated cell death pathway influenced by iron levels and cellular metabolism.

Purpose of the Study:

• To investigate the functional consequences of the TP53 P47S variant on macrophage iron metabolism and immune function.
• To explore the potential evolutionary advantages and disadvantages conferred by this variant in different disease contexts.

Main Methods:

• Utilized P47S human and mouse cell lines and macrophages.
• Performed proteomics analysis to assess macrophage signaling pathways.
• Administered iron chelators and liver X receptor (LXR) agonists to P47S mice.
• Analyzed clinical data correlating the P47S variant with iron biomarkers in African Americans.

Main Results:

• P47S macrophages exhibit iron accumulation, altered cytokine profiles, increased arginase, and decreased nitric oxide synthase activity.
• This phenotype enhances intracellular bacterial infections while providing protection against malaria-associated hemozoin.
• Proteomics revealed decreased LXR activation, inflammation, and antibacterial defense in P47S macrophages.
• Iron chelators and LXR agonists ameliorated bacterial infection response in P47S mice.
• Elevated iron biomarkers (transferrin, ferritin) were associated with higher P47S variant prevalence in African Americans.

Conclusions:

• The TP53 P47S variant induces iron dysregulation in macrophages, leading to a distinct immune phenotype.
• This phenotype presents a trade-off, offering protection against malaria but increasing vulnerability to bacterial pathogens.
• The findings suggest a potential role for the P47S variant in human iron homeostasis and adaptation to specific environments, such as malaria-endemic regions.