Human natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells.
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.
Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research and Technology, Singapore 138602.
Qingfeng
Q
Chen
Anburaj
A
Amaladoss
Weijian
W
Ye
Min
M
Liu
Sara
S
Dummler
Fang
F
Kong
Lan Hiong
LH
Wong
Hooi Linn
HL
Loo
Eva
E
Loh
Shu Qi
SQ
Tan
Thiam Chye
TC
Tan
Kenneth T E
KT
Chang
Ming
M
Dao
Subra
S
Suresh
Peter R
PR
Preiser
Jianzhu
J
Chen
D000818:Animals; D002448:Cell Adhesion; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology*; D051379:Mice; D018512:Parasitemia / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*
LFA-1; NK killing; humanized mouse model; malaria infection