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

Abstract

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

Pronounced in vivo hemoglobin polymerization in red blood cells of Gulf toadfish: a general role for hemoglobin aggregation in vertebrate hemoparasite defense?

“…Heterozygote Hb S carriers (with sickle cell trait and Hb AS RBCs) require much stronger degrees of Hb deoxygenation, plasma acidosis, and MCHC elevation for RBC sickling to occur (7). Hb AS heterozygotes are therefore usually free of clinical symptoms, and, as the best known example of a balanced polymorphism in humans, they have a greatly reduced relative risk of clinical P. falciparum malaria (10,20,40).…”

“…Hb AC heterozygotes show normal blood Hb levels and have some protection against clinical P. falciparum malaria (40). The mechanisms behind the protective effects of the Hb S and Hb C variants are incompletely understood but have been shown to include innate components at the RBC level (18,19,43,49), as well as acquired components (10,20). Each variant is thought to have arisen more than once in different malaria endemic regions (40).…”

Malaria Epidemiology at the Clone Level

“…Such studies are essential to evaluate vaccine candidates [30, 31]. Based on the same concept, the association between sickle-cell disease – a mutation in human hosts – and protection from clinical malaria was explored [32]. …”

Protection Against Malaria in Man: a Probe into some of the Implicated Mechanisms in Sub-Saharan Africa

“…Gong et al, demonstrated that in these patients, innate mechanisms induce reinforced protection against high parasitemia, and reinforced protection against outblown malaria infection, and that acquired immunity from repeated malaria infection further potentiates these effects [17].…”