Abstract
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Killer cell immunoglobulin-like receptors (KIR) and their HLA ligands influence the outcome of many infectious diseases. Data from a longitudinal cohort comprised of three study sites in Uganda with varying malaria transmission intensity show that presence of the HLA-C2 and HLA-Bw4 ligands for inhibitory KIR2DL1 and KIR3DL1, respectively, increase the likelihood of Plasmodium falciparum (Pf) parasitemia in an additive manner. For KIR2DL1/2/3, parasite prevalence was highest among individuals with KIR/HLA-C ligand pairs that are capable of the greatest cellular inhibition. Individuals homozygous for HLA-C2, which mediates strong inhibition via the near ubiquitous KIR2DL1 receptor, had the highest odds of parasitemia, while HLAC1/C2 heterozygotes had intermediate odds, and individuals homozygous for HLA-C1, which mediates weaker inhibition through KIR2DL2/3, had the lowest odds of parasitemia. A higher risk of parasitemia was also observed in the pairing of HLA-C1 with its receptor KIR2DL2 compared to its less inhibitory receptor KIR2DL3. Additionally, higher surface expression of HLA-C, the ligand for KIR2DL1/2/3, was associated with a higher likelihood of parasitemia. Together these data indicate that stronger KIR-mediated inhibition confers a higher risk of Pf parasitemia and suggest that KIR-expressing effector cells play a role in mediating anti-parasite immunity.