The toll-like receptor 1 variant S248N influences placental malaria

Abstract In malaria-endemic regions, Plasmodium falciparum infection in pregnancy is a predominant cause of maternal and infant morbidity and mortality. Primiparae are relatively immune-naive and particularly prone. Innate immune recognition of P. falciparum is partly mediated by Toll-like receptors (TLRs), and single nucleotide polymorphisms (SNPs) of TLR-4 and -9 influence manifestation. Recognition via TLR-2, which functions as heterodimer with TLR-1 or TLR-6, appears to be essential but in previous studies from Ghana, functional TLR-2 SNPs were virtually absent. In the present study, we assessed two well characterized TLR-1 polymorphisms, rs4833095 (S248N) and rs5743618 (I602S), among 302 primiparous Ghanaian women, and analysed associations with P. falciparum infection and manifestation. The prevalence of the TLR-1 S248N variant was 20.5%, whereas the TLR-1 I602S variant was rare at 2%. Placental P. falciparum infection was observed in 78% of women heterozygous for the TLR-1 S248N SNP but in 63% of women with the respective wildtype ( P  = 0.03). Furthermore, the odds of malaria-associated anaemia were more than doubled in TLR-1 S248N heterozygous women ( P  = 0.03) although parasite densities did not differ. No differences in the rates of low birth weight and preterm delivery were observed. These data support that TLR-1 is involved in the recognition of P. falciparum and indicate its role in susceptibility to and manifestation of malaria in pregnancy.