Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax

Chandra C. Ghosh, Aditi Mukherjee, Sascha David, Ulla G. Knaus, Deborah J. Stearns-Kurosawa, Shinichiro Kurosawa, Samir M. Parikh

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The anthrax lethal toxin (LT) enters host cells and enzymatically cleaves MAPKKs or MEKs. How these molecular events lead to death from anthrax remains poorly understood, but published reports suggest a direct effect of LT on vascular permeability. We have found that LT challenge in mice disrupts signaling through Tie-2, a tonically activated receptor tyrosine kinase in the endothelium. Genetic manipulations favoring Tie-2 activation enhanced interendothelial junctional contacts, prevented vascular leakage, and promoted survival following a lethal dose of LT. Cleavage of MEK1/2 was necessary for LT to induce endothelial barrier dysfunction, and activated Tie-2 signaled through the uncleaved fraction of MEKs to prevent LT's effects on the endothelium. Finally, primates infected with toxin-secreting Bacillus anthracis bacilli developed a rapid and marked imbalance in the endogenous ligands that signal Tie-2, similar to that seen in LT-challenged mice. Our results show that B. anthracis LT blunts signaling through Tie-2, thereby weakening the vascular barrier and contributing to lethality of the disease. Measurement of circulating Tie-2 ligands and manipulation of Tie-2 activity may represent future prognostic and therapeutic avenues for humans exposed to B. anthracis.

Original languageEnglish (US)
Pages (from-to)10024-10029
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number25
DOIs
StatePublished - Jun 19 2012
Externally publishedYes

Keywords

  • Angiopoietin
  • Edema
  • Infection

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax'. Together they form a unique fingerprint.

Cite this