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Effects of human natural killer (NK) cells on Plasmodium falciparum infected red cells
... LAMP-1 (CD107a) appears on the surface of effector cells following degranulation and can be used as a marker of cytotoxic activation (Alter et al., 2004). NK cells have previously been reported to lyse iRBC ( Chaicumpa et al., 1983;Orago and Facer, 1991) and induce expression of LAMP-1 following exposure to iRBC ( Korbel et al., 2005). Slight changes in NK cell activation status were detected after incubation with peptidic DBL-1a (a PfEMP-1 subdomain) which was proposed to bind the Natural Cytotoxicity Receptors NKp30 and NKp46 and induce NK cell cytotoxicity ( Mavoungou et al., 2007). ...
Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) is a variable antigen expressed by P. falciparum, the malarial parasite. PfEMP-1, present on the surface of infected host erythrocytes, mediates erythrocyte binding to vascular endothelium, enabling the parasite to avoid splenic clearance. In addition, PfEMP-1 is proposed to regulate host immune responses via interactions with the CD36 receptor on antigen-presenting cells. We investigated the immunoregulatory function of PfEMP-1 by comparing host cell responses to erythrocytes infected with either wild-type parasites or transgenic parasites lacking PfEMP-1. We showed that PfEMP-1 suppresses the production of the cytokine interferon-gamma by human peripheral blood mononuclear cells early after exposure to P. falciparum. Suppression of this rapid proinflammatory response was CD36 independent and specific to interferon-gamma production by gammadelta-T, NK, and alphabeta-T cells. These data demonstrate a parasite strategy for downregulating the proinflammatory interferon-gamma response and further establish transgenic parasites lacking PfEMP-1 as powerful tools for elucidating PfEMP-1 functions.
The biology of Natural Killer (NK) cells and other NK Receptor (NKR)(+) leukocytes has largely been elucidated in viral or cancer systems, and involvement in other diseases or infectious states is less clearly defined. Recently, however, clear evidence has emerged for a role in malaria. NK cells and NKR(+) leukocytes significantly control susceptibility and resistance to both malaria infection and severe disease syndromes in murine models, in dependence upon receptors encoded within the Natural Killer Complex (NKC). Plasmodium falciparum can rapidly activate human NKR(+) gammadelta T cells and NK cells in vitro, and these responses are controlled partly by NKR loci encoded within the human syntenic NKC and Killer Immunoglobulin-like Receptor (KIR) genomic regions. Neither erythrocytes nor malaria parasites express HLA or MHC Class I-like homologues, or obvious stress-type ligands, suggesting the possibility of novel NKR recognition mechanisms. Parasite-derived ligands such as P. falciparum Erythrocyte Membrane Protein-1 (PfEMP-1) and glycosylphosphatidylinositol (GPI) regulate some of these diverse responses. Population-based immunogenetic analyses should allow the identification of NKC and KIR loci controlling innate and adaptive immune responses to malaria and associated with altered risk of infection and disease.
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