Changes in mammalian copper homeostasis during microbial infection

Area of Science:

• Immunometabolism
• Nutrient Homeostasis
• Infectious Disease

Background:

• Copper (Cu) is an essential nutrient and a potential toxin, requiring tight homeostatic control.
• Infections can disrupt copper homeostasis, leading to significant changes in tissue and serum metal levels.
• Previous understanding of Cu dysregulation during infection, particularly in the liver and kidneys, was limited.

Purpose of the Study:

• To elucidate the mechanisms behind altered copper homeostasis during infection.
• To investigate the role of ceruloplasmin (Cp) in serum and liver copper changes during Candida albicans infection.
• To identify the pathways responsible for copper loss in the kidneys during infection.

Main Methods:

• Utilized wild-type and ceruloplasmin knockout (Cp-/-) mice infected with Candida albicans.
• Analyzed serum, liver, and kidney copper and iron levels at various stages of infection.
• Investigated the role of the copper-transporting ATPase ATP7B using Atp7b-/- mice.
• Examined copper homeostasis during infection with Plasmodium berghei to assess conserved mechanisms.

Main Results:

• Elevated serum copper during infection is primarily due to increased liver production of ceruloplasmin (Cp).
• Increased Cp levels contribute to the recovery of serum iron levels by facilitating transferrin loading.
• Cp accounts for elevated liver copper, but not kidney copper decline; ATP7B is not essential for this kidney copper loss.
• Similar serum copper increases and kidney copper decreases were observed during Plasmodium berghei infection, suggesting a common response.

Conclusions:

• Ceruloplasmin plays a critical role in modulating copper and iron homeostasis during infection.
• Kidney copper dynamics during infection involve mechanisms distinct from Cp and ATP7B.
• Altered copper homeostasis is a conserved host response across different types of infections, with potential implications for immunity.