Elly O. Munde, Winnie A. Okeyo, Samwel B. Anyona, Evans

Abstract

An understanding of the immunogenetic basis of naturally acquired immunity to Plasmodium falciparum infection would aid in the designing of a rationally based malaria vaccine. Variants within the Fc gamma receptors (Fc Rs) mediate immunity through engagement of immunoglobulin G and other immune mediators, such as gamma interferon (IFN- ), resulting in erythrophagocytosis and production of inflammatory cytokines in severe malarial anemia (SMA). The Toll-like receptors (TLRs) trigger transcription of proinflammatory cytokines and induce adaptive immune responses. Therefore, these receptors may condition malaria disease pathogenesis through alteration in adaptive and innate immune responses. To further delineate the impacts of Fc RIIIA and TLR9 in SMA pathogenesis, the associations between Fc RIIIA 176F/V and TLR9 1237T/C variants, SMA (hemoglobin [Hb] < 6.0 g/dl), and circulating IFN- levels were investigated in children (n 301) from western Kenya with acute malaria. Multivariate logistic regression analysis (controlling for potential confounders) revealed that children with the Fc RIIIA 176V/TLR9 1237C (VC) variant combination had 64% reduced odds of developing SMA (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.20 to 0.64; P 0.001), while carriers of the Fc RIIIA 176V/TLR9 1237T (VT) variant combination were twice as susceptible to SMA (OR, 2.04; 95% CI, 1.19 to 3.50; P 0.009). Children with SMA had higher circulating IFN- levels than non-SMA children (P 0.008). Hemoglobin levels were negatively correlated with IFN- levels (r 0.207, P 0.022). Consistently, the Fc RIIIA 176V/TLR9 1237T (VT) carriers had higher levels of circulating IFN- (P 0.011) relative to noncarriers, supporting the observation that higher IFN- levels are associated with SMA. These results demonstrate that Fc RIIIA-176F/V and TLR9 1237T/C variants condition susceptibility to SMA and functional changes in circulating IFN- levels.