Research ArticleINFECTIOUS DISEASES

Neutrophil extracellular traps drive inflammatory pathogenesis in malaria

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Science Immunology  18 Oct 2019:
Vol. 4, Issue 40, eaaw0336
DOI: 10.1126/sciimmunol.aaw0336

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Neutrophil-derived NETs make malaria worse

The role of neutrophils in the inflammation and tissue pathology associated with malaria infection is poorly understood. Knackstedt et al. used samples from patients infected with the Plasmodium falciparum parasite, as well as a mouse model of malaria, to investigate the contributions of neutrophils and neutrophil extracellular traps (NETs) to disease pathogenesis. Heme released from parasitized red blood cells induced formation of intravascular NETs, leading to an increase in emergency granulopoiesis and an enhancement in the capacity of endothelial cells to bind infected erythrocytes. These findings demonstrate that neutrophil-derived NETs exacerbate malarial immunopathology, opening the door to targeting NETs as part of human malaria therapy.

Abstract

Neutrophils are essential innate immune cells that extrude chromatin in the form of neutrophil extracellular traps (NETs) when they die. This form of cell death has potent immunostimulatory activity. We show that heme-induced NETs are essential for malaria pathogenesis. Using patient samples and a mouse model, we define two mechanisms of NET-mediated inflammation of the vasculature: activation of emergency granulopoiesis via granulocyte colony-stimulating factor production and induction of the endothelial cytoadhesion receptor intercellular adhesion molecule–1. Soluble NET components facilitate parasite sequestration and mediate tissue destruction. We demonstrate that neutrophils have a key role in malaria immunopathology and propose inhibition of NETs as a treatment strategy in vascular infections.

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