title: The triumph of good over evil: protection by the sickle gene against malaria.
abstract: The mechanisms underlying Plasmodium falciparum resistance in persons with sickle trait have been under active investigation for more than a half century. This Perspective reviews progress in solving this challenging problem, including recent studies that have exploited the genomics and proteomics of the parasite. The formation of Hb S polymer in the parasitized AS RBC leads to impaired parasite growth and development along with enhanced clearance from the circulation and reduced deposition in deep postcapillary vascular beds. Enhanced generation of reactive oxygen species in sickled AS RBCs is a pathogenetic feature shared by parasitized thalassemic and G6PD-deficient RBCs, triggering abnormal topology of the RBC plasma membrane with decreased and disordered display of PfEMP-1, a P falciparum adhesion protein critical for endothelial adherence. A mouse model of Hb S confers host tolerance to P berghei, through inhibition of pathogenic CD8(+) T cells and induction of heme oxygenase-1. An additional and apparently independent mode of protection is provided by the selective expression in AS RBCs of 2 species of microRNA that integrate into P falciparum mRNAs and inhibit translation and parasite growth.
authors.affiliation: Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. hfbunn@rics.bwh.harvard.edu
authors.forename: H Franklin
authors.initials: HF
authors.lastname: Bunn
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004910:Erythrocyte Membrane / Q000378:metabolism / Q000648:ultrastructure; D004913:Erythrocytes, Abnormal / Q000469:parasitology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000097:blood / Q000235:genetics / Q000469:parasitology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006801:Humans; D008288:Malaria / Q000097:blood / Q000453:epidemiology / Q000276:immunology / Q000469:parasitology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D010962:Plasmodium berghei / Q000502:physiology; D010963:Plasmodium falciparum / Q000235:genetics / Q000502:physiology; D015800:Protozoan Proteins / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D016053:RNA, Protozoan / Q000235:genetics; D017382:Reactive Oxygen Species / Q000097:blood; D012641:Selection, Genetic; D012805:Sickle Cell Trait / Q000097:blood / Q000235:genetics* / Q000469:parasitology; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000097:blood / Q000235:genetics / Q000469:parasitology
chemical_list: D051547:Heme Oxygenase-1; D006451:Hemoglobin, Sickle; D008565:Membrane Proteins; D035683:MicroRNAs; D015800:Protozoan Proteins; D012333:RNA, Messenger; D016053:RNA, Protozoan; D017382:Reactive Oxygen Species; D055544:beta-Globins; C525067:MIR223, human; C531201:MIRN451 microRNA, human; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; C496542:Hmox1 protein, mouse