Human natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells

Abstract

Immunodeficient mouse-human chimeras provide a powerful approach to study host-specific pathogens, such as Plasmodium falciparum that causes human malaria. Supplementation of immunodeficient mice with human RBCs supports infection by human Plasmodium parasites, but these mice lack the human immune system. By combining human RBC supplementation and humanized mice that are optimized for human immune cell reconstitution, we have developed RBC-supplemented, immune cell-optimized humanized (RICH) mice that support multiple cycles of P. falciparum infection. Depletion of human natural killer (NK) cells, but not macrophages, in RICH mice results in a significant increase in parasitemia. Further studies in vitro show that NK cells preferentially interact with infected RBCs (iRBCs), resulting in the activation of NK cells and the elimination of iRBCs in a contact-dependent manner. We show that the adhesion molecule lymphocyte-associated antigen 1 is required for NK cell interaction with and elimination of iRBCs. Development of RICH mice and validation of P. falciparum infection should facilitate the dissection of human immune responses to malaria parasite infection and the evaluation of therapeutics and vaccines. malaria infection | humanized mouse model | LFA-1 | NK killing

The Effect of Antiretroviral Naïve HIV-1 Infection on the Ability of Natural Killer Cells to Produce IFN-γ upon Exposure to Plasmodium falciparum-Infected Erythrocytes

“…As previously reportedly [18,19,21] , human NK cells from healthy people are known to produce IFN-γ after contact with iRBC. NK cells could also protect against malaria by lysing iRBC; however, during this study, NK cell activity was measured with the expression of IFN-γ after exposure to iRBC.…”

“…In addition to IFN-γ, NK cells have also been reported to produce granzyme B (GB) in response to Plasmodium species [18] . Moreover, NK cells have also been reported to directly lyse infected red blood cells (iRBC) [21] . Thus, the importance of NK cells in the control of early parasitaemia has been demonstrated in several reports [21,22] .…”

“…Moreover, NK cells have also been reported to directly lyse infected red blood cells (iRBC) [21] . Thus, the importance of NK cells in the control of early parasitaemia has been demonstrated in several reports [21,22] . However, in antiretroviral naïve HIV-1 infection, several functions of NK cells including cytokine production and cytolysis could be affected.…”

Macrophages Are the Determinant of Resistance to and Outcome of Nonlethal Babesia microti Infection in Mice

“…However, another study has shown that macrophage depletion results in a slight increase in parasitemia, with no significant change in the survival of mice infected with lethal or nonlethal Plasmodium yoelii during the acute phase of infection (18). Likewise, a recent study noted that the depletion of macrophages did not significantly alter the parasitemia of Plasmodium falciparum in humanized mice (24). The discrepancy with our observation might be explained based on the differences in the experimental designs of those studies, as we depleted the cells at different phases of infection but not at one consistent time point during infection.…”

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

“…NK cells are rapidly activated by malaria parasites, contribute to the early IFN-␥ response during blood-stage infection (64), and can eliminate infected erythrocytes in vivo in a contact-dependent manner (65). Importantly, there is a functional dichotomy: the rarer CD56bright cells are more prominent in lymphatic tissues and are superior cytokine producers, while the CD56dim subset harbors a stronger cytotoxic potential (66)(67)(68).…”