Multiple red cell variants are known to confer protection from malaria. Here, we review advances in identifying new variants that modulate malaria risk and in defining molecular mechanisms that mediate malaria protection.
New red cell variants, including an innate variant in the red cell's major Ca2+ pump and the acquired state of iron deficiency, have been associated with protection from clinical falciparum malaria. The polymorphisms hemoglobin C (HbC) and hemoglobin S (HbS) – known to protect carriers from severe falciparum malaria – enhance parasite passage to mosquitoes and may promote malaria transmission. At the molecular level, substantial advances have been made in understanding the impact of HbS and HbC upon the interactions between host microRNAs and Plasmodium falciparum protein translation; remodeling of red cell cytoskeletal components and transport of parasite proteins to the red cell surface; and chronic activation of the human innate immune system, which induces tolerance to blood-stage parasites. Several polymorphisms have now been associated with protection from clinical vivax malaria or reduced Plasmodium vivax density, including Southeast Asian ovalocytosis and two common forms of glucose-6-phosphate dehydrogenase deficiency.
Red cell variants that modulate malaria risk can serve as models to identify clinically relevant mechanisms of pathogenesis, and thus define parasite and host targets for next-generation therapies.
aDivision of Infectious Diseases and International Health, Duke Global Health Institute, Duke University Medical Center, Durham
bDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina
cLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Correspondence to Rick M. Fairhurst, MD, PhD, Laboratory of Malaria and Vector Research, NIAID/National Institutes of Health, 12735 Twinbrook Parkway, Room 3E-10A, Rockville, MD 20852, USA. Tel: +1 301 402 7393; e-mail: firstname.lastname@example.org