NK Cells: Uncertain Allies against Malaria

Abstract

Until recently, studies of natural killer (NK) cells in infection have focused almost entirely on their role in viral infections. However, there is an increasing awareness of the potential for NK cells to contribute to the control of a wider range of pathogens, including intracellular parasites such as Plasmodium spp. Given the high prevalence of parasitic diseases in the developing world and the devastating effects these pathogens have on large numbers of vulnerable people, investigating interactions between NK cells and parasitized host cells presents the opportunity to reveal novel immunological mechanisms with the potential to aid efforts to eradicate these diseases. The capacity of NK cells to produce inflammatory cytokines early after malaria infection, as well as a possible role in direct cytotoxic killing of malaria-infected cells, suggests a beneficial impact of NK cells in this disease. However, NK cells may also contribute to overproduction of pro-inflammatory cytokines and the consequent immunopathology. As comparatively little is known about the role of NK cells later in the course of infection, and growing evidence suggests that heterogeneity in NK cell responses to malaria may be influenced by KIR/HLA interactions, a better understanding of the mechanisms by which NK cells might directly interact with parasitized cells may reveal a new role for these cells in the course of malaria infection.

Keywords: KIR; NK cells; cytotoxic killing; inflammatory cytokines; malaria.

Figure 1

The intra-erythrocytic asexual replication cycle of malaria parasites. After initial infection of the host and replication in the liver, merozoites are released into the blood stream where they penetrate healthy erythrocytes. The merozoite will then metabolize host hemoglobin to fuel its own development into the mature schizont stage (over the course of approximately 48 h in the case of P. falciparum) while restructuring the erythrocytic membrane to aid in nutrient transfer, rosetting and sequestration, and producing proteins, some of which are exported to the erythrocyte surface. The mature schizont will then undergo replicative fission, forming 8–32 merozoites which lyse the cell membrane and re-enter the bloodstream.

Figure 2

Evidence of natural killer (NK) cells conjugating to malaria-infected erythrocytes. NK cells selectively form conjugates or “rosettes” with infected, but not uninfected, erythrocytes. Baratin et al. observed conjugate formation between the NK92 cell line and P. falciparum-infected erythrocytes by light microscopy (A). [Figure from Baratin et al. (118). Copyright under Creative Commons license CC-BY.] Korbel et al. observed conjugate formation via confocal microscopy (B) where NK cells from some donors showed actin relocalization to the site of contact with P. falciparum-infected erythrocytes, possibly indicating formation of an immune synapse. [Figure used with permission from Korbel et al. (113). Copyright 2005. The American Association of Immunologists, Inc.]

Figure 3

Hypothesized model for the continuing role of natural killer (NK) cells during malaria infection. NK cells may destroy infected hepatocytes by perforin/granzyme-mediated cytotoxic killing or death receptor-induced apoptosis, or may kill the parasite within the hepatocyte via cytokine-mediated induction of toxic radicals (A). During the early erythrocytic stage of infection, NK cells are activated by cytokines from macrophages and dendritic cells (DCs) and in turn release interferon gamma (IFN-γ) to activate macrophages that phagocytose infected erythrocytes (B). Once the adaptive immune response has developed, T cells contribute interleukin (IL)-2 to enhance the ongoing NK cell response. In the presence of specific IgG antibodies, NK cells may now mediate parasite clearance and killing by antibody-dependent cell-mediated cytotoxicity (ADCC). NK cells may also kill infected erythrocytes directly via formation of an immune synapse and release of cytolytic granules (C).