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May 31, 2010

Researchers Develop Approach in Mice to Treat Tularemia

  • A team of scientists report developing a compound that protects mice from infection with the bacterium that causes tularemia, a highly infectious disease of rodents that is sometimes transmitted to people. In experiments with human immune cells, the molecule also demonstrated protection against three other types of disease-causing bacteria that, like the tularemia bacteria, occur naturally, can be highly virulent, and are considered possible agents of bioterrorism.

    The experimental therapeutic works by stimulating the host immune system to destroy invading microbes. In contrast, antibiotics work by directly attacking invading bacteria, which often develop resistance to these medications. The drug candidate has the potential to enhance the action of antibiotics and provide an alternative to them.

    Catharine Bosio, Ph.D., and her colleagues at NIAID's Rocky Mountain Laboratories led the study. Collaborators are from Colorado State University in Fort Collins and Juvaris Biotherapeutics. The research is published online in PLoS Pathogens.

    In the study, the scientists combined components isolated from the membrane of a weakened strain of Francisella tularensis, the agent of tularemia, with the Juvaris product CLDC (cationic liposome DNA complexes). The combination stimulated reactive oxygen species (ROS) and reactive nitrogen species (RNS) in immune cells that ingest bacteria. ROS and RNS attack and kill invading bacteria, preventing replication and spread of the pathogens to other cells.

    Sixty percent of mice in the study survived pulmonary infection with virulent F. tularensis when treated with the therapeutic intravenously three days before the bacterial challenge. No mice survived when given the bacterial components or CLDC alone. The treatment also protected human immune cells from bacteria that cause plague, melioidosis, and brucellosis as well as tularemia. Melioidosis is primarily a tropical disease spread to humans and animals through contaminated soil and water. Brucellosis is a disease that primarily affects animals including humans who come in contact with infected animals or animal products such as contaminated milk.

    The three-day advance treatment appears crucial to providing enough time to stimulate the immune system, according to Dr. Bosio. Any treatment less than three days in advance failed to protect the mice, she said.

    “We are continuing to improve the versatility of this treatment as an antibacterial therapeutic with respect to timing of delivery and efficacy,” Dr. Bosio says. Her research group will continue to study the precise role that membrane protein fractions play in combination with CLDC and how the combination affects the production of RNS and ROS in cells from mice and from humans.


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