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

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.

SUBMITTER: Ghosh CC

PROVIDER: S-EPMC3382507 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Ghosh Chandra C CC Mukherjee Aditi A David Sascha S Knaus Ulla G UG Stearns-Kurosawa Deborah J DJ Kurosawa Shinichiro S Parikh Samir M SM

Proceedings of the National Academy of Sciences of the United States of America 20120604 25

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 vascu ...[more]

PMID: 22665799

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

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

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