Born to sweet delight: Using natural models of malaria protection to understand and neutralize P. falciparum pathogenesis

• Published in: PLoS pathogens Vol. 15; no. 6; p. e1007770
• Main Authors: Saelens, Joseph W, Taylor, Steve M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-06-2019; Public Library of Science (PLoS)
• Subjects: ABO system; Animals; Antigens; Biology and Life Sciences; Coevolution; Cytoskeleton; Elliptocytosis; Endothelium; Erythrocyte membrane protein 1; Erythrocytes; Genomes; Genomics; Glucose 6 phosphate dehydrogenase; Glucosephosphate dehydrogenase; Hemoglobin; Human behavior; Human genome; Humans; Hypotheses; Hypoxia; Infectious diseases; Leukocytes; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - enzymology; Malaria, Falciparum - genetics; Medical research; Medicine and Health Sciences; Membrane proteins; Models, Biological; Mutants; Mutation; Parasites; Pathogenesis; Pearls; Plasmodium falciparum; Plasmodium falciparum - enzymology; Plasmodium falciparum - genetics; Plasmodium falciparum - pathogenicity; Polypeptides; Prevention; Protein families; Proteins; Red blood cells; Surface antigens; Thalassemia; Tropical diseases; Vector-borne diseases; North Carolina; United States > US; Africa
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007770

The human genome harbors archived responses to the pressure of severe, life-threatening malaria, and chief among these are innate variants of erythrocytes, which serve as principal cellular hosts for the parasite. Since JBS Haldane first speculated that red blood cell (RBC) variants may confer some resistance to malaria, numerous studies using diverse approaches have identified an array of innate variants, which can be grouped as disorders of the erythrocyte cytoskeleton (e.g., Southeast Asian ovalocytosis), variation in erythrocyte surface antigens (e.g., ABO and Duffy), enzymatic aberrations (e.g., glucose-6-phosphate dehydrogenase deficiency), and mutants of α- or β-globin proteins, either as deletions (e.g., α-thalassemia) or point mutations (e.g., hemoglobin [Hb] S or C). Because of this, these models of naturally occurring protection need to be exploited to better understand the mechanisms of parasite pathogenesis and how these can be neutralized. [...]variants of erythrocytes are the principal known means by which humans have developed protection, most notably through mutations in Hb (Table 1). Cellular pathogenesis Cellular mechanisms of pathogenesis are principally governed by interactions between infected RBCs (iRBCs) and extracellular ligands on host cells, including endothelium, leukocytes, and uninfected RBCs; these interactions are enabled by the expression of parasite-derived proteins on the RBC surface, including the hypervariable protein families P. falciparum erythrocyte membrane protein 1 (PfEMP1), repetitive interspersed families of polypeptides (RIFIN), and subtelomeric variable open reading frame (STEVOR).