Toll-like receptor polymorphisms and cerebral malaria.

摘要

Cerebral malaria is a severe neurologic complication of P. falciparum infection which occurs in individuals with little or no acquired immunity to malaria, mostly children in endemic areas. Some cerebral malaria patients make a full recovery with the use of anti-malarial drugs, however the mortality rate is 18.6%, and 10.9% of recovering children have neurological deficits. The multi-factorial pathogenesis of cerebral malaria is characterized by sequestration of parasitized red blood cells within the cerebral microvasculature and an over-vigorous host pro-inflammatory response. Host genetic factors which influence the magnitude of pro-inflammatory response are likely to affect malaria disease outcome and be under selective pressure by malaria. Toll like receptors (TLRs) are activated by P. falciparum derived ligands to produce pro-inflammatory cytokines. Because of their role in the innate immune response to malaria, we hypothesized that genetic polymorphisms within TLR genes may affect susceptibility to cerebral malaria. In a case control study examining Ugandan children with cerebral malaria or uncomplicated malaria, we found that TLR polymorphisms differentially affected susceptibility to cerebral malaria, and this corresponded to altered proinflammatory responses. Heterozygosity for a 22 bp deletion in the first unstranslated exon of TLR2 was associated with protection from cerebral malaria (p=0.005, OR 0.34), and reduced pam3cys inducible TLR2 expression in vitro. Homozygosity for a TLR9 promoter SNP -1237T/C was associated with susceptibility to cerebral malaria (p=0.04, OR 3.69), and elevated serum IFN-gamma levels in vivo. We conclude that the protective TLR2 polymorphism was associated with potential dampening of pro-inflammatory responses, whereas, the susceptibility enhancing TLR9 SNP was associated with overvigorous pro-inflammatory responses in vivo. Despite the profound effects on susceptibility to cerebral malaria, we found no evidence that these TLR polymorphisms are under selective pressure by malaria according to allele frequencies in two Kenyan study sites with different malaria endemicity levels.