Neutrophil metalloproteinase driven spleen damage hampers infection control of trypanosomiasis

Hien Thi Thu Pham, Stefan Magez, Boyoon Choi, Bolortsetseg Baatar, Joohee Jung and Magdalena Radwanska ()
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Hien Thi Thu Pham: Ghent University Global Campus
Stefan Magez: Ghent University Global Campus
Boyoon Choi: Ghent University Global Campus
Bolortsetseg Baatar: Ghent University Global Campus
Joohee Jung: Duksung Women’s University
Magdalena Radwanska: Ghent University Global Campus

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Recent blood transcriptomic analysis of rhodesiense sleeping sickness patients has revealed that neutrophil signature genes and activation markers constitute the top indicators of trypanosomiasis-associated inflammation. Here, we show that Trypanosoma brucei infection results in expansion and differentiation of four splenic neutrophil subpopulations, including Mki67+Birc5+Gfi1+Cebpe+ proliferation-competent precursors, two intermediate immature subpopulations and Cebpb+Spi1+Irf7+Mcl1+Csf3r+ inflammation reprogrammed mature neutrophils. Transcriptomic scRNA-seq profiling identified the largest immature subpopulation by Mmp8/9 positive tertiary granule markers. We confirmed the presence of both metalloproteinases in extracellular spleen homogenates and plasma. During infection, these enzymes digest extracellular matrix components in the absence of sufficient TIMP inhibitory activity, driving remodeling of the spleen follicular architecture. Neutrophil depletion prevents the occurrence of organ damage, resulting in increased plasma cell numbers and prolonged host survival. We conclude that trypanosomiasis-associated neutrophil activation is a major contributor to the destruction of the secondary lymphoid architecture, required for maintaining an efficient adaptive immune response.

Date: 2023
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DOI: 10.1038/s41467-023-41089-w

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