Contributions of natural killer cells to the immune response against Plasmodium

Burrack, Kristina S.; Hart, Geoffrey T.; Hamilton, Sara E.

doi:10.1186/s12936-019-2953-1

Cited by 54 publications

(42 citation statements)

References 96 publications

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“…To determine which immune cells to study, we measured LILRB1 expression in peripheral white blood cells by antibody staining and flow cytometry, and found that, while LILRB1 is widely distributed, it is most prevalent in CD4 + T cells and NK cells ( Extended Data Figures 6 ). Of these, NK cells are most relevant in the context of malaria blood stage infection as they have recently been shown to interact with infected erythrocytes through antibody- dependent cell-mediated cytotoxicity (ADCC) 19 , 20 .…”

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confidence: 99%

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Harrison

Mørch

Felce

et al. 2020

Nature

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The Plasmodium species that cause malaria are obligate intracellular parasites, and disease symptoms occur as they replicate within human blood. Despite risking immune detection, the parasite delivers proteins that bind host receptors to infected erythrocyte surfaces. In the causative agent of the most deadly human malaria, Plasmodium falciparum, RIFINs form the largest erythrocyte surface protein family 1 . Some RIFINs can bind inhibitory immune receptors, acting as targets for unusual antibodies containing a LAIR1 ectodomain 2 - 4 , or as ligands for LILRB1 5 . RIFINs stimulate LILRB1 activation and signalling5, thereby potentially dampening human immune responses. To understand this process, we determined a structure of a RIFIN bound to LILRB1. We show that the RIFIN mimics the natural activating ligand of LILRB1, MHC class I, in its LILRB1-binding mode. A single RIFIN mutation disrupts the complex, blocks LILRB1 binding by all tested RIFINs and abolishes signalling in a reporter assay. In a supported lipid bilayer system, which mimics NK cell activation by antibody- dependent cell-mediated cytotoxicity, both RIFIN and MHC are recruited to the NK cell immunological synapse and reduce cell activation, as measured by perforin mobilisation. Therefore, LILRB1-binding RIFINs mimic the binding mode of the natural ligand of LILRB1 and suppress NK cell function.

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confidence: 99%

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Harrison

Mørch

Felce

et al. 2020

Nature

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“…Natural killer (NK) cells play an important role in the innate immune response to malaria infection (10,11). NK cells are the first cells in peripheral blood to produce interferon gamma (IFN-γ) in response to P. falciparum infection (11), and they have also been shown to participate in adaptive immunity.…”

Section: Introductionmentioning

confidence: 99%

Diversity of KIR genes and their HLA-C ligands in Ugandan populations with historically varied malaria transmission intensity

Tukwasibwe

Traherne

Chazara

et al. 2021

Preprint

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Background: Malaria is one of the most serious infectious diseases in the world. The malaria burden is greatly affected by human immunity, and immune responses vary between populations. Genetic diversity in KIR and HLA-C genes, which are important in immunity to infectious diseases, is likely to play a role in this heterogeneity. Several studies have shown that KIR and HLA-C genes influence the immune response to viral infections, but few studies have examined the role of KIR and HLA-C in malaria infection, and these have used low-resolution genotyping. The aim of this study was to determine whether genetic variation in KIR and their HLA-C ligands differ in Ugandan populations with historically varied malaria transmission intensity using more comprehensive genotyping approaches.Methods: High throughput multiplex quantitative real-time PCR method was used to genotype KIR genetic variants and copy number variation and a high-throughput real-time PCR method was developed to genotype HLA-C1 and C2 allotypes for 1,344 participants, aged 6 months to 10 years, enrolled from Ugandan populations with historically high (Tororo District), medium (Jinja District) and low (Kanungu District) malaria transmission intensity. Results: The prevalence of KIR3DS1, KIR2DL5, KIR2DS5 and KIR2DS1 genes was significantly lower in populations from Kanungu compared to Tororo (7.6% vs. 13.2%: p=0.006, 57.2% vs. 66.4%: p=0.005, 33.2% vs. 46.6%: p<0.001 and 19.7% vs. 26.7%: p=0.014 respectively) or Jinja (7.6% vs.18.1%: p<0.001, 57.2% vs. 63.8%: p=0.048, 33.2% vs. 43.5%: p=0.002 and 19.7% vs. 30.4%: p<0.001 respectively). The prevalence of homozygous HLA-C2 was significantly higher in populations from Kanungu (31.6%) compared to Jinja (21.4%), p=0.043, with no significant difference between Kanungu and Tororo (26.7%), p=0.296. Conclusions: The KIR3DS1, KIR2DL5, KIR2DS5 and KIR2DS1 genes may partly explain differences in transmission intensity of malaria since these genes have been positively selected for in places with historically high malaria transmission intensity. The high-throughput multiplex real-time HLA-C genotyping PCR method developed will be useful in disease association studies involving large cohorts.

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“…It has been demonstrated that the production of the regulatory cytokine IL-10 by NK cells prevents overt pathology and death from cerebral malaria in mouse models. 88 Fig. 2 NK receptors and responses to malaria.…”

Section: Introductionmentioning

confidence: 99%

Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria

et al. 2020

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Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIRs and HLAs in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIRs and HLAs associated with immunity to malaria thus far.

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Contributions of natural killer cells to the immune response against Plasmodium

Cited by 54 publications

References 96 publications

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Diversity of KIR genes and their HLA-C ligands in Ugandan populations with historically varied malaria transmission intensity

Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria

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