Abstract
As a leading cause of childhood mortality worldwide, selection pressure by Plasmodium falciparum continues to shape the human genome. Severe disturbances within the microcirculation result from the adhesion of infected erythrocytes to host receptors on monocytes, platelets, and endothelium. In this prospective study, we compared expression of all major host cytoadhesion receptors among Ugandan children presenting with uncomplicated malaria (n = 1078) versus children with severe malaria (n = 855), including cerebral malaria (n = 174), severe anaemia (n = 522), and lactic acidosis (n = 154). We report a significant survival advantage attributed to blood group O and increased monocyte expression of CD36 and ICAM1 (CD54). The high case fatality rate syndromes of cerebral malaria and lactic acidosis were associated with high platelet CD36 expression and thrombocytopenia, and severe malaria anaemia was characterized by low ICAM1 expression. In a logistic regression model of disease severity, odds ratios for the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were greater than that of sickle haemoglobin. Host genetic adaptations to Plasmodium falciparum suggest new potential malaria treatment strategies.
Highlights
We found the relative risk of fatal malaria to uncomplicated malaria (UM) was 2Á3-fold higher for group A or AB versus group O
We identified for the first time that group A1 (the wild-type with the highest A antigen expression (Berneman et al, 1991)) was over-represented in the severe malaria syndromes of cerebral malaria (CM) and isolated lactic acidosis (LA)
We found a surprising and significant association between lower monocyte ICAM1 expression in severe malaria anaemia (SMA) compared with other severe syndromes
Summary
This prospective case-control study enrolled children, age 6 months to 12 years, presenting with either initially severe or uncomplicated P falciparum malaria to Mulago Hospital’s Acute Care Unit in meso-endemic Kampala, Uganda between October 15, 2007 and October 30, 2009. Children with severe malnutrition were ineligible for enrolment. The malaria diagnosis was established first with clinical symptoms and a positive screening thick smear. Two blinded reviewers of thin and thick smears at a reference parasitology laboratory independently confirmed the diagnosis and parasite density using leucocyte counts (Figs 1–2 in supporting information). Approval for the study was granted by Makerere University Faculty of Medicine Research Ethics Committee, the Toronto Academic Health Science Network Research Ethics Board, and the Uganda National Council for Science and Technology. The study was registered as NCT 00707200 at www. The study was registered as NCT 00707200 at www. clinicaltrials.gov
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