Vaccines, Blood & Biologics
Researchers at the U.S. Food and Drug Administration (FDA) have shown how a protein called anthrax lethal toxin (LT) contributes to the symptoms caused by inhaling the spores of the bacterium Bacillus anthracis. Spores are inactive forms of certain types of bacteria that become active and reproduce after they enter the body.
The researchers showed that LT reduces production of claudin-5, a molecule that helps keep the cells making up blood vessels tightly connected to each other. This tight connection forms a barrier that prevents leakage of fluid from the blood. Claudin-5 works with another molecule, called VE-cadherin, to maintain this cellular barrier.
The finding that LT plays a key role in the disruption of this barrier by reducing claudin-5 levels is important because it contributes an important insight into how the toxin produces the symptoms of inhalation anthrax: swelling, bleeding, fluid buildup in the lungs, and inflammation of the blood vessels. This new insight could help researchers to develop therapies designed to slow or repair the severe damage to blood vessels that causes these symptoms.
The FDA scientists first investigated the role of LT in cell culture studies using microvascular endothelial cells--human cells that line the tiny blood vessels in the lung. The scientists grew the cells until they linked together and formed a sheet, or barrier. Following treatment with LT, the cells stopped making claudin-5 and the barrier formed by the cells weakened as the connections between them came undone. Moreover, the weakening of the barrier was not caused by cell death; nor was there an increase in the rate of claudin-5 breakdown. Instead, the gene coding for claudin-5 was much less active in making that protein. LT also reduced claudin-5 production in the livers of mice by about 75% after 72 hours.
The FDA scientists are with the Office of Blood Research and Review at the Center for Biologics Evaluation and Research. The work was funded in part by the agency’s Medical Countermeasures Initiative. The goal of MCMi is to ensure that drugs, vaccines, diagnostics, and other relevant equipment are available to help defend against chemical, biological, radiological, radiological, or nuclear attack, and emerging infectious disease threats.
“Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions”
April 2013/Volume 8/Issue4/e62576
Felice D’Agnillo1*, Matthew C. Williams1, Mahtab Moayeri3, Jason M. Warfel2
1Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland.
2Laboratory of Respiratory and Special Pathogens, Division of Bacterial, Parasitic and Allergenic Products, Office of Vaccine Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland.