Human natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells
Wong, Lan Hiong
Loo, Hooi Linn
Tan, Shu Qi
Tan, Thiam Chye
Chang, Kenneth T. E.
Preiser, Peter R.
Date of Issue2014
School of Biological Sciences
Singapore-MIT Alliance Programme
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.
Proceedings of the National Academy of Sciences of the United States of America
© The Author(s). This paper was published in Proceedings of the National Academy of Sciences of the United States of America and is made available as an electronic reprint (preprint) with permission of The Author(s). The paper can be found at the following official DOI: http://dx.doi.org/10.1073/pnas.1323318111. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.