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ResearchIn-Press PreviewImmunologyInfectious diseaseInflammation Open Access | 10.1172/jci.insight.198687

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

Pengjun Xi,1 Patrick A. Sandoz,2 Maximilian Julius Lautenbach,1 Eleni Bilev,3 Björn Önfelt,3 Anna Färnert,4 Quirin Hammer,5 and Christopher Sundling1

1Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden

2Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

3Department of Applied Physics, Karolinska Institutet, Stockholm, Sweden

4Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden, Stockholm, Kenya

5Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

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1Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden

2Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

3Department of Applied Physics, Karolinska Institutet, Stockholm, Sweden

4Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden, Stockholm, Kenya

5Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

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1Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden

2Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

3Department of Applied Physics, Karolinska Institutet, Stockholm, Sweden

4Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden, Stockholm, Kenya

5Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

Find articles by Lautenbach, M. in: PubMed | Google Scholar

1Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden

2Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

3Department of Applied Physics, Karolinska Institutet, Stockholm, Sweden

4Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden, Stockholm, Kenya

5Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

Find articles by Bilev, E. in: PubMed | Google Scholar

1Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden

2Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

3Department of Applied Physics, Karolinska Institutet, Stockholm, Sweden

4Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden, Stockholm, Kenya

5Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

Find articles by Önfelt, B. in: PubMed | Google Scholar

1Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden

2Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

3Department of Applied Physics, Karolinska Institutet, Stockholm, Sweden

4Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden, Stockholm, Kenya

5Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

Find articles by Färnert, A. in: PubMed | Google Scholar |

1Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden

2Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

3Department of Applied Physics, Karolinska Institutet, Stockholm, Sweden

4Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden, Stockholm, Kenya

5Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

Find articles by Hammer, Q. in: PubMed | Google Scholar

1Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden

2Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

3Department of Applied Physics, Karolinska Institutet, Stockholm, Sweden

4Division of Infectious Diseases, Karolinska Institute, Stockholm, Sweden, Stockholm, Kenya

5Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

Find articles by Sundling, C. in: PubMed | Google Scholar |

Published April 21, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.198687.
Copyright © 2026, Xi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 21, 2026 - Version history
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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 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.

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  • Version 1 (April 21, 2026): In-Press Preview
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