Genetic control of resistance to human malaria

Curr Opin Immunol. 2009 Oct;21(5):499-505. doi: 10.1016/j.coi.2009.04.001. Epub 2009 May 11.


The term 'innate resistance' covers mechanisms of resistance that operate early in the course of infections, preceding adaptive immune responses which exert effects after several days. The first example of genetically controlled innate resistance to human malaria was the demonstration in 1954 that sickle-cell heterozygotes have less severe Plasmodium falciparum infections than do children with normal adult hemoglobin. This observation has been repeatedly confirmed, most recently by independent studies of genome-wide associations in severe falciparum malaria, which have identified the HBB locus as the major signal of association. Other abnormal hemoglobins, glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency also confer some degree of resistance against falciparum malaria. A second early example of inherited innate resistance to malaria was the finding that nonexpression of the Duffy antigen/chemokine receptor (DARC) on erythrocytes confers resistance to P. vivax. However, this parasite can enter nonhuman primate red cells independently of DARC, and in some human populations P. vivax has been observed in persons lacking DARC. Hence DARC is not the only receptor for P. vivax, but it is likely to be a major one for human transmission. Innate resistance to malaria is rapidly reinforced by adaptive immune responses, both cell-mediated and humoral. Among the factors influencing the efficacy of adaptive immune responses to malaria is the MHC complex constitution of hosts. This differs among populations, presumably because of variations in the structure of parasite antigens recognized by the immune systems of hosts.

Publication types

  • Review

MeSH terms

  • Adult
  • Animals
  • Child
  • Duffy Blood-Group System / blood
  • Duffy Blood-Group System / genetics
  • Duffy Blood-Group System / immunology
  • Hemoglobins / metabolism
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Malaria / blood
  • Malaria / genetics
  • Malaria / immunology*
  • Plasmodium falciparum / immunology*
  • Plasmodium vivax / immunology*
  • Receptors, Cell Surface / blood
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology


  • ACKR1 protein, human
  • Duffy Blood-Group System
  • Hemoglobins
  • Receptors, Cell Surface