Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability.

Abstract

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication.

• Authors: Blandine Geny, Huot Khun, Catherine Fitting, Leticia Zarantonelli, Christelle Mazuet, Nadège Cayet, Marek Szatanik, Marie-Christine Prevost, Jean-Marc Cavaillon, Michel Huerre, Michel R Popoff
• Journal: The American journal of pathology (Am J Pathol) Vol. 170 Issue 3 Pg. 1003-17 (Mar 2007) ISSN: 0002-9440 [Print] United States
• PMID: 17322384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Toxins
• Cadherins
• Cytokines
• hemorrhagic toxin HT, Clostridium sordellii
• rac GTP-Binding Proteins

Topics

• Adherens Junctions (drug effects, pathology)
• Animals
• Bacterial Toxins (toxicity)
• Cadherins (drug effects)
• Capillary Permeability (drug effects)
• Cytokines (drug effects)
• Disease Models, Animal
• Edema, Cardiac (chemically induced, pathology)
• Endothelial Cells (drug effects, pathology)
• Heart (drug effects)
• Immunohistochemistry
• Lung (blood supply, drug effects, pathology)
• Male
• Mice
• Microscopy, Electron, Transmission
• Pulmonary Edema (chemically induced, pathology)
• Shock, Septic (chemically induced)
• rac GTP-Binding Proteins (drug effects)