Severe infectious diseases are often characterized by an overwhelming and unbalanced systemic immune response to microbial infections. Human antithrombin (hAT) is a crucial coagulation inhibitor with anti-inflammatory activities. Here we identify three hAT-binding proteins (CD13, CD300f and LRP-1) on human monocytes that are involved in blocking the activity of nuclear factor-κB. We found that the modulating effect is primarily restricted to the less abundant β-isoform (hβAT) of hAT that lacks N-glycosylation at position 135. Individuals with a mutation at this position have increased production of hβAT and analysis of their blood, which was stimulated ex vivo with lipopolysaccharide, showed a decreased inflammatory response. Similar findings were recorded when heterozygotic mice expressing hAT or hβAT were challenged with lipopolysaccharide or infected with Escherichia coli bacteria. Our results finally demonstrate that in a lethal E. coli infection model, survival rates increased when mice were treated with hβAT one hour and five hours after infection. The treatment also resulted in a reduction of the inflammatory response and less severe organ damage.
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The data that support the findings of this study are available from the corresponding author on request.
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This work was supported in part by the Alfred Österlund Foundation (to P.P. and H.H.), the Crafoord Foundation (grant no. 20180506 to P.P.), the Knut and Alice Wallenberg Foundation (grant no. 2011.0037 to H.H.), the Medical Faculty at Lund University (to H.H.), the Swedish Foundation for Strategic Research (grant no. SB12-0019 to A.E. and H.H.), the Swedish Research Council (grant no. 2013-3078 to A.E. and grant no. 2016-01104 to H.H.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors thank R. Bhongir for performing the microarray assays, M. Baumgarten for her help with the electron microscopy experiments, J. Martin for his support in the generation of mice expressing hAT and hβAT and Lund University Bioimaging Centre.
P.P., A.E., G.K. and H.H. have filed a provisional patent on the possibility of using hβAT as an antimicrobial treatment. All other authors have no competing interests.
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Papareddy, P., Rossnagel, M., Doreen Hollwedel, F. et al. A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection. Nat Microbiol 4, 2442–2455 (2019). https://doi.org/10.1038/s41564-019-0559-6
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