Significant Association of KIR2DL3-HLA-C1 Combination with Cerebral Malaria and Implications for Co-evolution of KIR and HLA

Kouyuki Hirayasu,Jun Ohashi,Masahiro Satake,Atsuko Ogawa,Hisashi Arase,Koichi Kashiwase,Toshio Yabe,Peter Parham,Hathairad Hananantachai,Jintana Patarapotikul,Kazunori Nakajima,Katsushi Tokunaga,Izumi Naka,Minoko Takanashi,James W Kazura

doi:10.1371/journal.ppat.1002565

Abstract

Cerebral malaria is a major, life-threatening complication of Plasmodium falciparum malaria, and has very high mortality rate. In murine malaria models, natural killer (NK) cell responses have been shown to play a crucial role in the pathogenesis of cerebral malaria. To investigate the role of NK cells in the developmental process of human cerebral malaria, we conducted a case-control study examining genotypes for killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands in 477 malaria patients. We found that the combination of KIR2DL3 and its cognate HLA-C1 ligand was significantly associated with the development of cerebral malaria when compared with non-cerebral malaria (odds ratio 3.14, 95% confidence interval 1.52–6.48, P = 0.00079, corrected P = 0.02). In contrast, no other KIR-HLA pairs showed a significant association with cerebral malaria, suggesting that the NK cell repertoire shaped by the KIR2DL3-HLA-C1 interaction shows certain functional responses that facilitate development of cerebral malaria. Furthermore, the frequency of the KIR2DL3-HLA-C1 combination was found to be significantly lower in malaria high-endemic populations. These results suggest that natural selection has reduced the frequency of the KIR2DL3-HLA-C1 combination in malaria high-endemic populations because of the propensity of interaction between KIR2DL3 and C1 to favor development of cerebral malaria. Our findings provide one possible explanation for KIR-HLA co-evolution driven by a microbial pathogen, and its effect on the global distribution of malaria, KIR and HLA.

Highlights

Malaria is a serious infectious disease, affecting over 300 million people and causing more than 1 million deaths annually worldwide [1]
When non-cerebral severe and mild malaria were merged into one group as non-cerebral malaria, the most significant association was obtained with the combination of KIR2DL3 and human leukocyte antigen (HLA)-C1 and cerebral malaria, as compared to the non-cerebral malaria group
These associations are presumably due to HLA-C group 1 (HLA-C1), because the carrier frequencies of HLA-C1 were significantly higher in the cerebral malaria group, compared with the non-cerebral malaria group, but those of HLA-C group 2 (HLA-C2) were not significantly low (Table 2)

Summary

Introduction

Malaria is a serious infectious disease, affecting over 300 million people and causing more than 1 million deaths annually worldwide [1]. NK cells are an early source of IFN-c in response to malaria infection [5,6], and this cytokine is known to be potentially involved in the pathogenesis of cerebral malaria [7,8,9]. NK cells show differences in responsiveness to P. falciparum-infected erythrocytes among malaria-naive donors [6,10,11], suggesting the presence of a genetic determinant for heterogeneous NK responsiveness. These observations have suggested that the genes encoding NK receptors and their ligands have critical roles in the development of cerebral malaria in humans

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Results

Conclusion