Discrete and conserved inflammatory signatures drive thrombosis in different organs after Salmonella infection

Marisol Perez-Toledo, Nonantzin Beristain-Covarrubias, Jamie Pillaye, Ruby R. Persaud, Edith Marcial-Juarez, Sian E. Jossi, Jessica R. Hitchcock, Areej Alshayea, William M. Channell, Niek T. J. Wiersma, Rachel E. Lamerton, Dean P. Kavanagh, Agostina Carestia, William G. Horsnell, Ian R. Henderson, Nigel Mackman, Andrew R. Clark, Craig N. Jenne, Julie Rayes, Steve P. Watson () and Adam F. Cunningham ()
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Marisol Perez-Toledo: University of Birmingham
Nonantzin Beristain-Covarrubias: University of Birmingham
Jamie Pillaye: University of Birmingham
Ruby R. Persaud: University of Birmingham
Edith Marcial-Juarez: University of Birmingham
Sian E. Jossi: University of Birmingham
Jessica R. Hitchcock: University of Birmingham
Areej Alshayea: University of Birmingham
William M. Channell: University of Birmingham
Niek T. J. Wiersma: University of Birmingham
Rachel E. Lamerton: University of Birmingham
Dean P. Kavanagh: University of Birmingham
Agostina Carestia: University of Calgary
William G. Horsnell: University of Cape Town
Ian R. Henderson: University of Queensland
Nigel Mackman: University of North Carolina at Chapel Hill
Andrew R. Clark: University of Birmingham
Craig N. Jenne: University of Calgary
Julie Rayes: University of Birmingham
Steve P. Watson: University of Birmingham
Adam F. Cunningham: University of Birmingham

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Inflammation-induced thrombosis is a common consequence of bacterial infections, such as those caused by Salmonella Typhimurium (STm). The presentation of multi-organ thrombosis post-infection that develops and resolves with organ-specific kinetics raises significant challenges for its therapeutic control. Here, we identify specific inflammatory events driving thrombosis in the spleens and livers of STm-infected mice. IFN-γ or platelet expression of C-type lectin-like receptor CLEC-2, key drivers of thrombosis in liver, are dispensable for thrombosis in the spleen. Platelets, monocytes, and neutrophils are identified as core constituents of thrombi in both organs. Depleting either neutrophils or monocytic cells abrogates thrombus formation. Neutrophils and monocytes secrete TNF and blocking TNF diminishes both thrombosis and inflammation, which correlates with reduced endothelial expression of E-selectin and leukocyte infiltration. Moreover, inhibiting tissue factor and P-selectin glycoprotein ligand-1 pathways impairs thrombosis in both spleen and liver. Therefore, we identify organ-specific, and shared mechanisms driving thrombosis within a single infection. This may inform on tailoring treatments towards infection-induced inflammation, and single- or multi-organ thrombosis, based on the clinical need.

Date: 2025
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DOI: 10.1038/s41467-025-57466-6

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