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      NK cells inhibit Plasmodium falciparum growth in red blood cells via antibody-dependent cellular cytotoxicity

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          Abstract

          Antibodies acquired naturally through repeated exposure to Plasmodium falciparum are essential in the control of blood-stage malaria. Antibody-dependent functions may include neutralization of parasite–host interactions, complement activation, and activation of Fc receptor functions. A role of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells in protection from malaria has not been established. Here we show that IgG isolated from adults living in a malaria-endemic region activated ADCC by primary human NK cells, which lysed infected red blood cells (RBCs) and inhibited parasite growth in an in vitro assay for ADCC-dependent growth inhibition. RBC lysis by NK cells was highly selective for infected RBCs in a mixed culture with uninfected RBCs. Human antibodies to P. falciparum antigens PfEMP1 and RIFIN were sufficient to promote NK-dependent growth inhibition. As these results implicate acquired immunity through NK-mediated ADCC, antibody-based vaccines that target bloodstream parasites should consider this new mechanism of action.

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          Malaria is a deadly disease caused by a parasite transmitted by mosquitoes. The parasite infects red blood cells, causing fever with flu-like symptoms. In some people, particularly pregnant women and children, the disease may be very serious and even lead to death. An effective malaria vaccine is urgently needed because malaria parasites are developing resistance to current drugs.

          People living in areas where malaria is common develop specific proteins called antibodies that protect them from malaria. Learning more about how the antibodies achieve this, could help to develop better vaccines. Scientists already know some antibodies bind to the malaria parasites and prevent them from entering red blood cells. Some vaccines have been based on these antibodies. Other antibodies bind to infected cells flagging them for destruction by cells of the immune system. Immune cells called natural killer cells can eliminate viruses or cancer cells this way, but it was not clear if they could also eliminate malaria parasite-infected red blood cells.

          Now, Arora et al. show that natural killer cells can selectively destroy malaria-infected red blood cells flagged with antibodies from people who live in areas where malaria is common. In laboratory experiments, natural killer cells from US volunteers, who were never exposed to malaria, did not kill normal or malaria-infected red blood cells. Adding antibodies collected from malaria-resistant volunteers from Africa allowed these natural killer cells from unexposed people to selectively seek out and destroy malaria-infected cells and leave uninfected red blood cells intact.

          Arora et al. also found that the antibodies from the malaria-resistant volunteers bound to parasite proteins on the surface of infected blood cells. The experiments suggest that vaccines designed to stimulate the production of antibodies to malaria proteins that are displayed on infected red blood cells, could destroy the parasite in infected people and help prevent disease and save lives.

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          Most cited references32

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          Gamma-globulin and acquired immunity to human malaria.

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            Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion.

            Freshly isolated, resting natural killer (NK) cells are generally less lytic against target cells than in vitro interleukin 2 (IL-2)-activated NK cells. To investigate the basis for this difference, the contribution of several receptors to activation of human NK cells was examined. Target-cell lysis by IL-2-activated NK cells in a redirected, antibody-dependent cytotoxicity assay was triggered by a number of receptors. In contrast, cytotoxicity by resting NK cells was induced only by CD16, and not by NKp46, NKG2D, 2B4 (CD244), DNAM-1 (CD226), or CD2. Calcium flux in resting NK cells was induced with antibodies to CD16 and, to a weaker extent, antibodies to NKp46 and 2B4. Although NKp46 did not enhance CD16-mediated calcium flux, it synergized with all other receptors. 2B4 synergized with 3 other receptors, NKG2D and DNAM-1 each synergized with 2 other receptors, and CD2 synergized with NKp46 only. Resting NK cells were induced to secrete tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), and to kill target cells by engagement of specific, pair-wise combinations of receptors. Therefore, natural cytotoxicity by resting NK cells is induced only by mutual costimulation of nonactivating receptors. These results reveal distinct and specific patterns of synergy among receptors on resting NK cells.
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              Activation, coactivation, and costimulation of resting human natural killer cells.

              Natural killer (NK) cells possess potent perforin- and interferon-gamma-dependent effector functions that are tightly regulated. Inhibitory receptors for major histocompatibility complex class I display variegated expression among NK cells, which confers specificity to individual NK cells. Specificity is also provided by engagement of an array of NK cell activation receptors. Target cells may express ligands for a multitude of activation receptors, many of which signal through different pathways. How inhibitory receptors intersect different signaling cascades is not fully understood. This review focuses on advances in understanding how activation receptors cooperate to induce cytotoxicity in resting NK cells. The role of activating receptors in determining specificity and providing redundancy of target cell recognition is discussed. Using Drosophila insect cells as targets, we have examined the contribution of individual receptors. Interestingly, the strength of activation is not determined simply by additive effects of parallel activation pathways. Combinations of signals from different receptors can have different outcomes: synergy, no enhancement over individual signals, or additive effects. Cytotoxicity requires combined signals for granule polarization and degranulation. The integrin leukocyte function-associated antigen-1 contributes a signal for polarization but not for degranulation. Conversely, CD16 alone or in synergistic combinations, such as NKG2D and 2B4, signals for phospholipase-C-gamma- and phosphatidylinositol-3-kinase-dependent degranulation.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                26 June 2018
                2018
                : 7
                : e36806
                Affiliations
                [1 ]deptLaboratory of Immunogenetics National Institute of Allergy and Infectious Diseases, National Institutes of Health RockvilleUnited States
                [2 ]deptDepartment of Medicine University of Minnesota MinneapolisUnited States
                [3 ]deptLaboratory of Malaria Immunology and Vaccinology National Institute of Allergy and Infectious Diseases, National Institutes of Health RockvilleUnited States
                [4 ]deptMalaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako BamakoMali
                [5 ]deptLaboratory of Malaria and Vector Research National Institute of Allergy and Infectious Diseases, National Institutes of Health RockvilleUnited States
                [6]Howard Hughes Medical Institute, Washington University School of Medicine United States
                [7]Howard Hughes Medical Institute, Washington University School of Medicine United States
                Author notes
                [†]

                BioMedicine Design, Pfizer Inc., Cambridge, United States.

                Author information
                http://orcid.org/0000-0003-0575-6205
                http://orcid.org/0000-0001-7261-3437
                https://orcid.org/0000-0002-4483-5005
                http://orcid.org/0000-0003-2150-2483
                http://orcid.org/0000-0002-7793-3728
                Article
                36806
                10.7554/eLife.36806
                6019063
                29943728
                54cd6248-4a4d-4f84-b543-01f1b1152aa9

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 20 March 2018
                : 31 May 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: Z01 AI000525-30 LIG
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Immunology and Inflammation
                Microbiology and Infectious Disease
                Custom metadata
                Red blood cells infected by the malaria parasite Plasmodium falciparum are destroyed by human natural killer cells in the presence of antibodies from people who have acquired clinical immunity to malaria.

                Life sciences
                human,p.falciparum,adcc,nk,rbc
                Life sciences
                human, p.falciparum, adcc, nk, rbc

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