Flavin-deficient erythrocytes offer protection against malaria parasites

Studies from the 1980s and 1990s conducted in Italy, where malaria was once endemic, hypothesized that individuals with erythrocytes deficient in flavin mononucleotide and flavin adenine dinucleotide (FAD)-collectively known as flavins-are partially protected against malaria. The condition was reported to be familial, consistent with a genetic element. This hypothesis, however, has never been tested. Using an erythrocyte FAD-dependent glutathione reductase activity assay, we identified individuals with flavin-deficient erythrocytes (FDE) in Ferrara, Italy (23% of 150 individuals screened), and in Huye, Rwanda (13% of 169 individuals). None of the individuals with FDE had a dietary riboflavin deficiency. Importantly, FDE from individuals in Ferrara, as well as erythrocytes depleted of flavins in vitro by riboflavin starvation, inhibited the intraerythrocytic proliferation of Plasmodium falciparum. We provide evidence that these erythrocytes are susceptible to oxidative stress, potentially explaining their inhibitory effect on parasite proliferation. Genetic analysis identified mutations in the FAD synthase gene of three individuals with FDE from Huye, consistent with a potential genetic basis.