NK cell cytotoxicity is transiently enhanced during acute malaria and modulated by the host microenvironment
Pengjun Xi, Patrick A. Sandoz, Maximilian Julius Lautenbach, Eleni Bilev, Björn Önfelt, Anna Färnert, Quirin Hammer, Christopher Sundling
Pengjun Xi, Patrick A. Sandoz, Maximilian Julius Lautenbach, Eleni Bilev, Björn Önfelt, Anna Färnert, Quirin Hammer, Christopher Sundling
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Research Article Immunology Infectious disease Inflammation

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

Abstract

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 patients with malaria in a nonendemic 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 downmodulates it after treatment. Understanding this balance between activation and suppression may inform strategies to harness NK cells for malaria control while minimizing immunopathology.

Authors

Pengjun Xi, Patrick A. Sandoz, Maximilian Julius Lautenbach, Eleni Bilev, Björn Önfelt, Anna Färnert, Quirin Hammer, Christopher Sundling

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Figure 4

Temporal dynamics of NK cell effector molecule and cytokine abundance.

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Temporal dynamics of NK cell effector molecule and cytokine abundance. (...
(A) Plasma levels of granzymes A, B, and H at acute infection (pink, n = 72), 10 days after treatment (light pink, n = 27), and 12 months after treatment (green, n = 33), measured as normalized protein expression (NPX) were repurposed from Lautenbach et al. (34). (B) Plasma concentrations of NK cell–activating cytokines (IL-12, IL-15, IL-18) and general inflammatory cytokines (TNF, IL-6, IL-10, IL-27, IFN-γ) across the same time points from the same dataset. LOD indicates average assay plate limit of detection ± SD for each protein. (C) Spearman correlation matrix showing pairwise relationships between cytokines and granzymes at the acute time point. (D) Summary of correlations between acute-phase protein levels (ΔNPX from acute to 12 months) and NK cell subset frequencies over time (acute to 12 months) as presented in Supplemental Figure 2. Subsets are defined by CD56, CD16, and CD57 expression. Symbols: (+) = positive expression; (–) = no expression, (b) = bright; (m) = dim; (N) = Not measured. Statistical analyses in A and B were performed using linear mixed-effects models accounting for repeated measures. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.