Killer‐cell immunoglobulin‐like receptors and malaria caused by Plasmodium falciparum in The Gambia

L.‐M Yindom,D J Conway,M Jallow,D Jeffries,O Janha,R Forbes,M Walther,P Aka

doi:10.1111/j.1399-0039.2011.01818.x

Abstract

The relevance of innate immune responses to Plasmodium falciparum infection, in particular the central role of natural killer (NK) cell-derived interferon gamma (IFN-γ), is becoming increasingly recognised. Recently, it has been shown that IFN-γ production in response to P. falciparum antigens is in part regulated by killer-cell immunoglobulin-like receptor (KIR) genes, and a study from malaria-exposed Melanesians suggested an association between KIR genotypes and susceptibility to infection. This prompted us to determine and compare the frequencies of 15 KIR genes in Gambian children presenting with either severe malaria (n = 133) or uncomplicated malaria (n = 188) and in cord-blood population control samples (n = 314) collected from the same area. While no significant differences were observed between severe and uncomplicated cases, proportions of individuals with KIR2DS2+C1 and KIR2DL2+C1 were significantly higher among malaria cases overall than in population control samples. In an exploratory analysis, activating KIR genes KIR2DS2, KIR3DS1 and KIR2DS5 were slightly higher in children in disease subgroups associated with the highest mortality. In addition, our data suggest that homozygosity for KIR genotype A might be associated with different malaria outcomes including protection from infection and higher blood parasitaemia levels in those that do get infected. These findings are consistent with a probable role of KIR genes in determining susceptibility to malaria, and further studies are warranted in different populations.

Highlights

Infection with the malaria parasite Plasmodium falciparum can result in asymptomatic parasite carriage, an uncomplicated febrile disease or a potentially life-threatening illness
Considering that expression of killercell immunoglobulin-like receptor (KIR) receptors on natural killer (NK) cells has been associated with the magnitude of IFN-γ responses to malaria parasites [14], we explored whether the ratio of inhibitory over activating KIR genes (I/A ratio) or the carriage of a particular KIR genotype is associated with parasite load measured on admission
We determined the presence or absence of 15 KIR genes in two groups of children infected with the malaria parasite P. falciparum with distinct disease outcomes and in a population control group

Summary

Introduction

Infection with the malaria parasite Plasmodium falciparum can result in asymptomatic parasite carriage, an uncomplicated febrile disease or a potentially life-threatening illness. Apart from clinical immunity that gradually develops with repeated exposure [1], human genetic variation influences clinical outcome in response to parasite encounter [2]. Epidemiological data from Kenya have indicated that about 25% of the risk of being infected with malaria parasites can be attributed to human genetic variation [3]. Natural killer (NK) cells are a key component of innate immunity. They kill their targets (diseased cells) by means. Activation of NK cells is explained by the ‘missing self’ hypothesis [6], where the lack of major histocompatibility complex (MHC) class I molecules on infected or malignant cells is sensed by NK cell surface receptors, or activating NK cell receptors interact with stressinduced molecules on the surface of altered cells [4]. While most pathogens can activate NK cells, down-regulation of MHC class I molecules is not a common feature of many infectious diseases, and it is increasingly recognised that most pathogens predominantly activate NK cells via an indirect pathway, with activating signals (both soluble and contact-dependent) being provided by accessory cells, such as dendritic cells, macrophages and/or monocytes [7]

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