Genetic and nutritional disturbances of folate metabolism modulate the outcome of cerebral malaria

Folates are B vitamins that are required for the synthesis of nucleotides and amino acids, and for methylation reactions. A common polymorphism in methylenetetrahydrofolate reductase (MTHFR, 677C>T), results in enzymatic deficiency and increased risk for several disorders. This polymorphism exists at high frequencies in many populations. Malaria is a parasitic infection that affects nearly 200 million people per year. The folate pathway has been a popular pharmacological target for anti-malarial therapies for many years and, more recently, there has been increased folate intake due to food fortification and vitamin supplementation in many countries. We questioned whether genetic or nutritional disturbances in folate metabolism would affect the response to malarial infection in mice.Mthfr+/- mice fed standard mouse chow were protected against Plasmodium berghei ANKA infection (cerebral malaria). These mice survived longer than Mthfr+/+ mice and had tissue-specific changes in expression of interferon-γ (IFNγ), peroxisome proliferator-activated receptor-γ (PPARγ) and interleukin-10 (IL-10). Mthfr+/- mice also had increases in total splenocytes, total T cells, CD4+ and CD8+ T cells, and in CCR4+ NK cells. Uninfected Mthfr+/- mice had changes in immune cell distribution and cytokine expression. Mice that over-express MTHFR (MTHFRTg) were more susceptible to P. berghei ANKA infection when fed standard mouse chow. They died more quickly and had decreases in their NK and CCR4+ NK cells, compared with their wild-type littermates. Uninfected MTHFRTg mice had decreases in total splenocytes, total T cells, and CD8+ T cells. Mthfr+/- and Mthfr+/+ mice fed amino acid-defined control diets (CD, recommended folate level) or folic acid-supplemented diets (FASD, 10-fold higher than recommended) had no survival differences. However, FASD mice died more quickly and had higher parasitemia compared with CD mice. Infected FASD mice had lower numbers of total splenocytes, total T cells, and lower numbers of specific T and NK cell sub-populations. These differences due to diet are similar to those seen in the study of genotype differences. FASD mice also had increased brain TNFα and increased Bcl-xl/Bak ratios in the liver that suggested they were more susceptible to P. berghei ANKA infection. We conclude that genetic or dietary disturbances in folate metabolism result in decreased parasite replication, an altered immune response and increased resistance to malaria in mice. These findings support our hypothesis that MTHFR 677C>T may have reached high frequencies in human populations as a result of the selective advantage it may have conferred against malaria. This work also has relevance for malaria-endemic regions when considering folic acid fortification or supplementation programs.

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