Evidence that interferon-γ plays a protective role during cerebral malaria

Background. The pathogenic mechanisms of cerebral malaria ( CM) are unclear but are thought to involve cytokine-mediated inflammation enhanced by parasite sequestration in the brain microcirculation. The role that interferon (IFN)-gamma could play that would enhance inflammation but also reduce parasitemia is unclear. Methods. Plasma IFN-gamma concentrations were measured by enzyme-linked immunosorbent assay in 96 children with CM and 40 children with uncomplicated malaria (UM) who had been recruited from Gabriel Toure Hospital (Bamako, Mali). We investigated the relationship between IFN-gamma concentrations and disease by nonparametric analysis. Polymorphisms in IFNG were characterized by restriction enzyme analysis or size-determination electrophoresis. Associations between polymorphisms and CM were evaluated by the family-based association test on 240 families. Results. During episodes of malaria, IFN-g concentrations were lower in children with CM than in children with UM (P = .007). IFNG-183T (P = .009) and IFNG-183G/T (P = .013) were found to be less frequent than expected in children with CM. A trend toward association was also observed between IFNG(CA)(14)/(CA)(14) (P = .073) and CM. The IFNG-183G/T and IFNG(CA)(14)/(CA)(14) genotypes were more frequent in children with UM than in children with CM (odds ratio, 0.30 and 0.34, respectively). Conclusions. The low plasma IFN-gamma concentrations in children with CM and the associations between a reduced risk of CM and (1) the IFNG-183T allele (which increases gene transcription) and (2) the IFNG-183G/ T genotype are consistent with the concept that IFN-gamma protects against CM.