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Scientists Turn Plague Protein Against Disease By Chris Schneidmiller WASHINGTON — A tool used by plague bacteria to spread infection may ultimately be the key to developing the first safe and effective vaccine against the pathogen, according to a research article published last week by scientists from the University of Chicago (see GSN, June 14). While plague continues to occur naturally, a more recent fear is that it would be used in an act of bioterrorism. Terrorists could develop an aerosolized version of pneumonic plague, which infects the lungs and can be passed from person to person. Pneumonic plague would kill anyone infected who did not receive antibiotics shortly after exposure, according to a University of Chicago Hospitals press release. The possibility of terrorists acquiring such a contagious weapon has created “an urgent need for vaccine development to protect humans against bubonic and pneumonic plague,” researchers wrote in a paper published in the August edition of Infection and Immunity. Plague has been used historically as a primitive weapon, with infected bodies catapulted into cities or used to taint water supplies. However, it would take “a lot of training and a lot of equipment” to turn the plague bacteria into a sophisticated weapon, said university Microbiology Department research associate Melanie Marketon. Both the United States and Soviet Union worked with pneumonic plague during the Cold War, according to a release by the U.S. Army Medical Research Institute of Infectious Diseases. “It’s been used as a weapon in the past, and I would certainly say it could be done again,” Marketon said in an interview. Plague bacteria could be collected from humans or animals that had become infected naturally, said David Withum, Centers for Disease Control and Prevention bioterrorism preparedness coordinator in Fort Collins, Colo. Still, high levels of scientific expertise would be needed to weaponize the germ, he said. U.S. laboratories that work with plague use multiple layers of security to ensure the bacteria are not misused, Marketon said. The U.S. Patriot Act also mandates restrictions on access to select agents such as plague, anthrax and ricin. Marketon said she expects that laboratories in other nations have developed similar safeguards. The Chicago scientists, with a colleague from Michigan State University, published two papers on the plague. One focuses on the method by which the bacteria overcome a body’s immune system. The other looks at how a protein used in the infection process could be turned against the plague. Researchers exposed mice to the plague, and then examined the animals’ spleens two to three days later, according to an article published online July 28 in Science Express. They found that the large majority of infected cells were macrophages, neutrophils or dendretic cells — the components of the “innate” immune system that provides a body’s first line of defense against infection. Those cells are supposed to break up bacteria and present them for elimination by the more powerful T and B cells. The “adaptive” immune system can take up to 10 days to fully respond. “By that time, with plague, the host is dead,” study author Olaf Schneewind, university microbiology chairman, said in the press release. Identifying the specific cells targeted by the bacteria could help researchers develop drugs to counteract that destructive interaction, thus bolstering the immune system, Marketon said. There is no direct evidence yet that the plague infection process in mice occurs identically in humans, but previous animal testing and reports on human plague victims indicate similarities, Marketon said. The plague bacterium injects its toxins into a cell through a needle-like extension. Key to the process is the LcrV protein, which helps puncture the cell membrane and suppresses the cell’s immune response, according to the Infection and Immunity article. “Without it, the bacteria are relatively harmless,” Schneewind said in the release. Researchers previously have found that the protein’s harmful effect on the immune system would block its use as a vaccine, the paper states. The University of Chicago scientists tested 11 versions of the protein, each time removing a different set of 30 amino acids. Testing found that one version produced infection-neutralizing antibodies that protected mice against higher than lethal doses of the bacteria while doing minimal damage to the immune response. “Our data provide the first evidence of plague vaccines that do not suppress innate immune responses … and that may be useful for plague vaccination in animals, and, perhaps, humans,” the paper states. Further animal testing is anticipated in developing the vaccine, according to the press release. Preparing it for actual use against bioterror would take years, said researcher Katie Overheim. “This isn’t something that will be a vaccine two weeks from now,” she said. “We’re still just in the beginning phases.”
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