Evidence for both innate and acquired mechanisms of protection from Plasmodium falciparum in children with sickle cell trait.

Sickle cell trait (HbAS) is known to be protective against Plasmodium falciparum malaria, but it is unclear when during the course of infection this protection occurs and whether protection is innate or acquired. To address these questions, a cohort of 601 children 1-10 years of age were enrolled in Kampala, Uganda, and followed for 18 months for symptomatic malaria and asymptomatic parasitemia. Genotyping was used to detect and follow individual parasite clones longitudinally within subjects. Children with HbAS were protected against the establishment of parasitemia, as assessed by the molecular force of infection at older but not younger ages (at 2 years of age: incidence rate ratio [IRR] = 1.16; 95% confidence interval [95% CI], 0.62-2.19; P = .6; at 9 years of age: IRR = 0.50; 95% CI, 0.28-0.87; P = .01), suggesting an acquired mechanism of protection. Once parasitemic, children with HbAS were less likely to progress to symptomatic malaria, with protection again being the most pronounced at older ages (at 2 years of age: relative risk [RR] = 0.92; 95% CI, 0.77-1.10; P = .3; at 9 years of age: RR = 0.68; 95% CI, 0.51-0.91; P = .008). Conversely, the youngest children were best protected against high parasite density (at 2 years of age: relative density = 0.24; 95% CI, 0.10-0.54; P = .001; at 9 years of age: relative density = 0.59; 95% CI, 0.30-1.19; P = .14), suggesting an innate mechanism of protection against this end point.

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria.

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.