Plasma biomarkers of hemoglobin loss in Plasmodium falciparum-infected children identified by quantitative proteomics

Anemia is common among young children infected with Plasmodium falciparum (Pf) and severe malarial anemia (SMA) is a major cause of their mortality. Two major mechanisms cause malarial anemia: hemolysis of uninfected as well as infected erythrocytes and insufficient erythropoiesis. In a longitudinal birth cohort in Mali, we commonly observed marked hemoglobin reductions during Pf infections with a small proportion that progressed to SMA. We sought biomarkers of these processes using quantitative proteomic analysis on plasma samples from 9 P. falciparum-infected children, comparing those with reduced hemoglobin (with or without SMA) versus those with stable hemoglobin. We identified higher plasma levels of circulating 20S proteasome and lower IGF-1 levels in children with reduced hemoglobin. We confirmed these findings in independent ELISA-based validation studies of subsets of children from the same cohort (20S proteasome, N=71; IGF-1, N=78). We speculate that circulating 20S proteasome plays a role in digesting erythrocyte membrane proteins modified by oxidative stress, resulting in hemolysis, while decreased IGF-1, a critical factor for erythroid maturation, might contribute to insufficient erythropoiesis. Quantitative plasma proteomics identified soluble mediators that may contribute to the major mechanisms underlying malarial anemia.