The study, published today in the journal Nature Communications, found that iron promotes growth and virulence of the malaria parasite Plasmodium falciparum through modulation of a host protein called heme oxygenase-1 or HO-1.
Iron-rich diets and intravenous iron supplementation have been associated with increased malaria incidence, parasitemia and severe disease in multiple epidemiological studies. Pregnant women, with their increased iron requirements, are at a greater risk of developing anemia as well as severe malaria, which underscores the need to understand the relationship between iron status, HO-1 and malaria pathogenesis.
"Malaria parasites utilize host-derived heme from hemoglobin digestion for their growth and development, and free heme has deleterious effects on the host," said corresponding author Dr. Elizabeth Winzeler. "Previous work from our laboratory identified HO-1 as a critical host protein that degrades heme to reduce the toxic effects of free heme and prevent severe malaria in mice. In the current study, we sought to determine how iron status might modulate these processes."
The researchers found that iron availability increases the expression of HO-1 in macrophages, which are cells that play an important role in the immune response to malaria. HO-1 expression was enhanced by the iron-dependent induction of the transcription factor Nrf2, which regulates the expression of a variety of genes involved in cellular defense against oxidative stress.
The increased HO-1 expression led to increased production of biliverdin, which is a product of heme degradation. Biliverdin can be converted to bilirubin, which has antioxidant and anti-inflammatory properties.
The researchers found that treatment with bilirubin reduced the growth of malaria parasites in vitro and in vivo. Furthermore, they found that mice with higher levels of HO-1 and biliverdin were more resistant to malaria infection.
These findings suggest that iron-induced HO-1 expression and biliverdin production may be important mechanisms by which iron promotes the growth and virulence of P. falciparum and that HO-1 and biliverdin may represent novel therapeutic targets for the treatment of malaria.
"Further investigation is needed to determine whether HO-1 induction and biliverdin production could be targeted therapeutically to treat or prevent malaria, particularly in patients with iron overload or during pregnancy," Winzeler said. "HO-1 expression and biliverdin production could also serve as biomarkers to monitor malaria disease progression and treatment response."
