Decreased Natural Killer Cell Function in Pediatric Severe Malaria in Areas of Higher Transmission

Abstract

Natural killer (NK) cells inhibit Plasmodium falciparum parasite growth through antibody-dependent cellular cytotoxicity (ADCC) in vitro. Research conducted in malaria-endemic regions has demonstrated that memory-like NK cells are elevated in individuals exposed to malaria, exhibit enhanced ADCC activity, and correlate with reduced parasitemia and protection against uncomplicated malaria. However, the role of NK cells in pediatric severe malaria (SM) is not known. To evaluate the NK cell phenotype and function in SM, we used flow cytometry to evaluate CD56 bright, CD56 dim, and CD56 neg NK cell subsets in Ugandan children 6 months – 4 years of age with SM (cerebral malaria (CM), n=11), severe malarial anemia (SMA), n=10) and asymptomatic community children as controls (CC, n=19). Children were enrolled from sites of moderate (Jinja) and low (Kampala) malaria transmission. Analysis revealed that children with SM had a lower proportion of total NK cells and CD56 bright NK cells; however, absolute counts of NK cells per ml did not differ. In addition, LILRB1, an inhibitory receptor, was the only phenotypic marker whose proportions were significantly increased in children with SM compared to CC. Functionally, children with SM had a higher proportion of degranulating (CD107a+, IFN-γ-) memory-like NK cells. However, memory-like NK cell subsets from children with SM had a lower proportion of interferon-γ only (CD107a-, IFN-γ+)-production than CC. In addition, when comparing malaria transmission intensities with NK cell function, NK cells of children with SM in moderate transmission area exhibited a lower proportion of degranulation compared to the area of low transmission. Conversely, in low malaria transmission areas, NK cells of children with SM demonstrated a higher proportion of degranulation compared to CC. These findings elucidate distinct functional differences in NK cells among children with SM in areas of low versus moderate malaria transmission.