NK cell cytotoxicity is transiently enhanced during acute malaria and modulated by the host microenvironment

Natural killer (NK) cells are pivotal in the early immune response to Plasmodium falciparum infection, yet their functional dynamics and regulation remain incompletely understood. In a longitudinal study of malaria patients in a non-endemic setting, we observed a transient but potent activation of NK cell cytotoxicity during acute malaria, characterized by rapid granzyme B-mediated killing and elevated expression of genes associated with cytotoxicity (PRF1, GZMB, and GZMA). This heightened activity was supported by increased plasma levels of granzymes and proinflammatory cytokines, which enhanced NK cell function in vitro. However, plasma samples from clinical malaria also contained inhibitory mediators, including soluble cytokine receptors, which dampened NK cell responses. These findings reveal that the host microenvironment orchestrates a tightly regulated NK cell response that potentiates cytotoxicity during acute infection and rapidly downmodulate it after treatment. Understanding this balance between activation and suppression may inform strategies to harness NK cells for malaria control while minimizing immunopathology.