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A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in
D Fernandez-Reyes1, A G Craig, S A Kyes
1Institute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
Abstract:
The malarial parasite Plasmodium falciparum has acted as a potent selective force on the human genome. The particular virulence of this organism is thought to be due to the adherence of parasitised red blood cells to small vessel endothelium through several receptors, including CD36, thrombospondin and intercellular adhesion molecule 1 (ICAM-1, CD54), and parasite isolates differ in their ability to bind to each. Immunohistochemical studies have implicated ICAM-1 as of potential importance in the pathogenesis of cerebral malaria, leading us to reason that if any single receptor were involved in the development of cerebral malaria, then in view of the high mortality of that complication, natural selection should have produced variants with reduced binding capacity. We therefore sequenced the N-terminal domain of ICAM-1 from a number of Africans and discovered a single mutation present at high frequency. Genotypes at this locus from samples from a case-control study indicated an association of the polymorphism with the severity of clinical malaria such that individuals homozygous for the mutation have increased susceptibility to cerebral malaria with a relative risk of two. These counterintuitive results have implications for the mechanism of malaria pathogenesis, resistance to other infectious agents and transplantation immunology.
Insights
A Plasmodium falciparum malaria mutation in intercellular adhesion molecule 1 (ICAM-1) increases susceptibility to severe cerebral malaria. This finding impacts understanding of malaria pathogenesis and host-pathogen interactions.
Area of Science:
- Genetics
- Immunology
- Infectious Disease
Background:
- Plasmodium falciparum malaria exerts significant selective pressure on the human genome.
- Parasitized red blood cell adherence to endothelium via receptors like ICAM-1 contributes to malaria virulence.
- ICAM-1 is implicated in cerebral malaria pathogenesis.
Purpose of the Study:
- To investigate the role of ICAM-1 in cerebral malaria.
- To identify genetic variations in ICAM-1 associated with malaria severity.
- To understand the evolutionary impact of malaria on human genetic resistance.
Main Methods:
- Sequencing of the N-terminal domain of ICAM-1 in African populations.
- Genotyping analysis of ICAM-1 polymorphisms in a case-control study.
- Statistical analysis to determine associations between genotypes and malaria severity.
Main Results:
- A high-frequency single mutation was discovered in the ICAM-1 gene.
- Individuals homozygous for this ICAM-1 mutation showed a two-fold increased risk of cerebral malaria.
- The polymorphism is associated with increased susceptibility to severe clinical malaria.
Conclusions:
- The ICAM-1 mutation represents a genetic adaptation to malaria, paradoxically increasing susceptibility to severe outcomes.
- Findings offer insights into malaria pathogenesis and host resistance mechanisms.
- The study has implications for infectious disease resistance and transplantation immunology.