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

• Published in: Blood 2022-04, Vol.139 (15), p.2361-2376
• Main Authors: Mahamar, Almahamoudou, Gonzales Hurtado, Patricia A., Morrison, Robert, Boone, Rachel, Attaher, Oumar, Diarra, Bacary S., Gaoussou, Santara, Issiaka, Djibrilla, Dicko, Alassane, Duffy, Patrick E., Fried, Michal
• Format: Article
• Language: English
• Subjects: Anemia - etiology; Biomarkers; Child; Child, Preschool; Hemoglobins; Hemolysis; Humans; Insulin-Like Growth Factor I; Malaria; Malaria, Falciparum - complications; Plasmodium falciparum; Proteasome Endopeptidase Complex; Proteomics; Red Cells, Iron, and Erythropoiesis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021014045

Anemia is common among young children infected with Plasmodium falciparum 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 P falciparum 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) vs those with stable hemoglobin. We identified higher plasma levels of circulating 20S proteasome and lower insulin-like growth factor-1 (IGF-1) levels in children with reduced hemoglobin. We confirmed these findings in independent enzyme-linked immunosorbent assay-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, whereas 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. This study was registered at www.clinicaltrials.gov as #NCT01168271. •Higher c-20S proteasome and lower IGF-1 levels are associated with hemoglobin drops in children with P falciparum infections.•Known activities of c-20S proteasome and IGF-1 levels suggest roles in hemolysis and insufficient erythropoiesis. [Display omitted]