RESUMEN
Genetic factors are likely to contribute to low severe malaria case fatality rates in Melanesian populations, but association studies can be underpowered and may not provide plausible mechanistic explanations if significant associations are detected. In preparation for a genome-wide association study, 29 candidate single-nucleotide polymorphisms (SNPs) with minor allele frequencies >5% were examined in a case-control study of 504 Papua New Guinean children with severe malaria. In parallel, an immunological substudy was performed on convalescent peripheral blood mononuclear cells (PBMCs) from cases and controls. Following stimulation with a Toll-like receptor (TLR) 1/2 agonist, effector cytokines and chemokines were assayed. The only significant genetic association observed involved a nonsynonymous SNP (TLR1rs4833095) in the TLR1 gene. A recessive (TT) genotype was associated with reduced odds of severe malaria of 0.52 (95% confidence interval (0.29-0.90), P=0.006). Concentrations of pro-inflammatory cytokines interleukin-1ß and tumour necrosis factor α were significantly higher in severe malaria cases compared with healthy controls, but lower in children with the protective recessive (TT) genotype. A genetic variant in TLR1 may contribute to the low severe malaria case fatality rates in this region through a reduced pro-inflammatory cellular phenotype.
Asunto(s)
Malaria Falciparum/genética , Malaria Falciparum/inmunología , Receptor Toll-Like 1/genética , Receptor Toll-Like 1/inmunología , Estudios de Casos y Controles , Preescolar , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Leucocitos Mononucleares/inmunología , Malaria Falciparum/parasitología , Masculino , Papúa Nueva Guinea , Polimorfismo de Nucleótido SimpleRESUMEN
Over a century ago, the malaria expedition of the brilliant microbiologist Robert Koch to the Dutch East Indies (Indonesia) and German New Guinea (now Papua New Guinea, or PNG), resulted in profound observations that are still central to our current understanding of the epidemiology and acquisition of immunity to the malaria parasite Plasmodium. The tradition of malaria research in PNG pioneered by Koch continues to this day, with a number of recent studies still continuing to elucidate his original concepts and hypotheses. These include age and exposure-related acquisition of immunity, species-specific and cross-species immunity, correlates of protective immunity and determining the prospects for anti-malaria vaccines.
