A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection

Praveen Papareddy, Madlen Rossnagel, Femke Doreen Hollwedel, Gülcan Kilic, Srinivas Veerla, Clément Naudin, Emanuel Smeds, Johannes Westman, Irene Martinez-Martinez, Arne Egesten, Maria Eugenia de la Morena-Barrio, Javier Corral, Adam Linder, Andrea Artoni, Maria Abbattista, Cristina Novembrino, Cord Herbert Brakebusch, Ida Martinelli, Gopinath Kasetty, Heiko Herwald

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2442-2455
JournalNature Microbiology
Volume4
Issue number12
DOIs
Publication statusPublished - 2019

Fingerprint

Antithrombins
Bacterial Infections
Protein Isoforms
Lipopolysaccharides
Antithrombin Proteins
Escherichia coli Infections
Infection
Glycosylation
Communicable Diseases
Monocytes
Carrier Proteins
Anti-Inflammatory Agents
Escherichia coli
Bacteria
Mutation

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Papareddy, P., Rossnagel, M., Doreen Hollwedel, F., Kilic, G., Veerla, S., Naudin, C., ... Herwald, H. (2019). A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection. Nature Microbiology, 4(12), 2442-2455. https://doi.org/10.1038/s41564-019-0559-6

A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection. / Papareddy, Praveen; Rossnagel, Madlen; Doreen Hollwedel, Femke; Kilic, Gülcan; Veerla, Srinivas; Naudin, Clément; Smeds, Emanuel; Westman, Johannes; Martinez-Martinez, Irene; Egesten, Arne; de la Morena-Barrio, Maria Eugenia; Corral, Javier; Linder, Adam; Artoni, Andrea; Abbattista, Maria; Novembrino, Cristina; Herbert Brakebusch, Cord; Martinelli, Ida; Kasetty, Gopinath; Herwald, Heiko.

In: Nature Microbiology, Vol. 4, No. 12, 2019, p. 2442-2455.

Research output: Contribution to journalArticle

Papareddy, P, Rossnagel, M, Doreen Hollwedel, F, Kilic, G, Veerla, S, Naudin, C, Smeds, E, Westman, J, Martinez-Martinez, I, Egesten, A, de la Morena-Barrio, ME, Corral, J, Linder, A, Artoni, A, Abbattista, M, Novembrino, C, Herbert Brakebusch, C, Martinelli, I, Kasetty, G & Herwald, H 2019, 'A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection', Nature Microbiology, vol. 4, no. 12, pp. 2442-2455. https://doi.org/10.1038/s41564-019-0559-6
Papareddy, Praveen ; Rossnagel, Madlen ; Doreen Hollwedel, Femke ; Kilic, Gülcan ; Veerla, Srinivas ; Naudin, Clément ; Smeds, Emanuel ; Westman, Johannes ; Martinez-Martinez, Irene ; Egesten, Arne ; de la Morena-Barrio, Maria Eugenia ; Corral, Javier ; Linder, Adam ; Artoni, Andrea ; Abbattista, Maria ; Novembrino, Cristina ; Herbert Brakebusch, Cord ; Martinelli, Ida ; Kasetty, Gopinath ; Herwald, Heiko. / A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection. In: Nature Microbiology. 2019 ; Vol. 4, No. 12. pp. 2442-2455.
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