Publication: A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection
Authors
Papareddy, Praveen ; Rossnagel, Madlen ; Hollwedel, Femke ; Kilic, Gülcan ; Veerla, Srinivas ; Naudin, Clément ; Smeds, Emanuel ; Westman, Johannes ; Martínez-Martínez, Irene ; Egesten, Arne ; Morena-Barrio, María Eugenia de la ; Corral, Javier ; Linder, Adam ; Artoni, Andrea ; Abbattista, Maria ; Novembrino, Cristina ; Brakebusch, Cord Hebert ; Martinelli, Ida ; Kasetty, Gopinath ; Herwarld, Heiko
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Publisher
Nature Research
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DOI
https://doi.org/10.1038/s41564-019-0559-6
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info:eu-repo/semantics/article
Description
© The Author(s), under exclusive licence to Springer Nature Limited 2019.
This document is the Published version of a Published Work that appeared in final form in Nature Microbiology. To access the final edited and published work see
https://doi.org/10.1038/s41564-019-0559-6
Abstract
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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Citation
Nature Microbiology, vol. 4 (2019), 2442–2455
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