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Neutrophil metalloproteinase driven spleen damage hampers infection control of trypanosomiasis

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  • Hien Thi Thu Pham

    (Ghent University Global Campus
    Ghent University
    Vrije Universiteit Brussel)

  • Stefan Magez

    (Ghent University Global Campus
    Vrije Universiteit Brussel
    Ghent University)

  • Boyoon Choi

    (Ghent University Global Campus
    Vrije Universiteit Brussel
    Ghent University)

  • Bolortsetseg Baatar

    (Ghent University Global Campus)

  • Joohee Jung

    (Duksung Women’s University)

  • Magdalena Radwanska

    (Ghent University Global Campus
    Ghent University)

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.

Suggested Citation

  • Hien Thi Thu Pham & Stefan Magez & Boyoon Choi & Bolortsetseg Baatar & Joohee Jung & Magdalena Radwanska, 2023. "Neutrophil metalloproteinase driven spleen damage hampers infection control of trypanosomiasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41089-w
    DOI: 10.1038/s41467-023-41089-w
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    1. Dorien Mabille & Laura Dirkx & Sofie Thys & Marjorie Vermeersch & Daniel Montenye & Matthias Govaerts & Sarah Hendrickx & Peter Takac & Johan Van Weyenbergh & Isabel Pintelon & Peter Delputte & Louis , 2022. "Impact of pulmonary African trypanosomes on the immunology and function of the lung," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Emma M. Briggs & Federico Rojas & Richard McCulloch & Keith R. Matthews & Thomas D. Otto, 2021. "Single-cell transcriptomic analysis of bloodstream Trypanosoma brucei reconstructs cell cycle progression and developmental quorum sensing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Juan F. Quintana & Praveena Chandrasegaran & Matthew C. Sinton & Emma M. Briggs & Thomas D. Otto & Rhiannon Heslop & Calum Bentley-Abbot & Colin Loney & Luis de Lecea & Neil A. Mabbott & Annette MacLe, 2022. "Single cell and spatial transcriptomic analyses reveal microglia-plasma cell crosstalk in the brain during Trypanosoma brucei infection," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
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