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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • University of Veterinary Medicine Hannover
  • University of Copenhagen
  • Maggiore Hospital Policlinico
  • Lund University
  • Hospital for Sick Children, Toronto
  • University of Murcia
  • Sahlgrenska Academy
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Infektionsmedicin
Originalspråkengelska
Sidor (från-till)1-14
TidskriftNature Microbiology
StatusE-pub ahead of print - 2019 sep 23
PublikationskategoriForskning
Peer review utfördJa