A new malaria killer: Fc receptor gamma chain and PLZF identify NK cell subsets that correlate with reduced Plasmodium falciparum parasitemia and increased antibody dependent cellular cytotoxicity against opsonized infected RBCs.

Abstract

Plasmodium falciparum (P.f) infection is a major cause of morbidity and mortality world-wide where symptoms and death occur as a result of the blood stage of the P.f. life cycle. To date, there is no effective blood stage malarial vaccine. Natural Killer (NK) cells are key players in the control of hematopoietic cancers and viral infections, however their role in blood stage malaria is unknown. We undertook a comprehensive analysis of NK cell phenotype and function in a cohort of subjects from a malaria clinical study in Mali, Africa. Using an unbiased analysis of different NK cell subsets, we found three major findings: 1. Fc receptor gamma chain (−) or PLZF (−) NK cells correlate with reduced parasitemia 2. Fc receptor gamma chain (−) NK cells correlate with protection from malaria symptoms 3. Fc receptor gamma chain (−) NK cells are enhanced for antibody dependent cellular cytotoxicity (ADCC). Antibodies are known to be protective in malaria, however the mechanism of this protection is still being elucidated. We hypothesized Fc receptor gamma chain (−) NK cells may be clearing opsonized, malaria-infected RBCs in vivo via ADCC. We show that Fc receptor gamma chain (−) NK cells specifically release lytic granules in response to opsonized, infected RBCs. This work indicates the host may increase the number of Fc receptor gamma chain (−) NK cells to aide in clearance of infected RBCs through ADCC. Because the antigens on the surface of infected RBCs are different than the invading parasite, these results could improve the identification of effective targets for blood stage vaccines.