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Scientist Receives $1.6 Million NIH Grant

ALBANY, N.Y., October 14, 2008 — Timothy Sellati, Ph.D., associate professor in the Center for Immunology and Microbial Disease at Albany Medical College, has received a $1.6 million grant from the National Institute of Allergy and Infectious Disease (National Institutes of Health) to continue studying whether lessening the immune response to a deadly form of bacteria could actually prevent death.

“It kind of runs counter to what we think. Our bodies mount immune responses to bacteria in an effort to get rid of them. What people may not realize, however, is that in some cases, that immune response might do more harm than good. With respiratory tularemia, this is the case,” says Dr. Sellati, who will be collaborating with scientists at the University of Alabama at Birmingham and the US Army Medical Research Institute for Infectious Disease (USAMRIID).

“The government is interested in this work, and tularemia in particular, because the bacteria has been weaponized in the past by both the United States and the former Soviet Union, and there is concern it could be used by bioterrorists,” says Dr. Sellati. Naturally occurring cases of tularemia usually enter through the bloodstream after contact with contaminated soil, diseased animals or tick bites. It’s a mild disease easily treated with antibiotics. In contrast, when inhaled into the lungs, F. tularensis, particularly genetically-altered or weaponized forms, are almost always lethal.

“At Albany Med, we are also actively working on vaccines for this form of tularemia, but this particular research is focused on finding an effective treatment for it,” says Dr. Sellati.

Dr. Sellati explains that when we are infected with bacteria like Francisella tularensis (which causes tularemia), among other responses, our bodies send special blood cells called neutrophils (white blood cells) to attack and eliminate the invading pathogen.

“A byproduct of this immune response is tissue damage (inflammation), which is responsible for the symptoms we feel when we are sick. With many diseases, the inflammation is tolerable, the neutrophils do their job, and we get better. However, in some cases, including infection with F. tularensis, the inflammation is excessive, and causes more harm than good,” says Dr. Sellati. He says F. tularensis has figured out a way to actually enter and survive inside the neutrophils making it harder for them to eliminate the bacteria. “But, the neutrophils keep trying to do their job and keep accumulating in the lungs, causing more and more inflammation with a reduced ability to kill the bacteria. The result is death,” he says.

But, the question of how to reduce the inflammation while still getting the benefit of the immune response remained. Dr. Sellati and his team focused on a protein that regulates the migration of neutrophils from the bloodstream into the lung, wondering what would happen if that regulator, called Matrix Metalloproteinase 9 (MMP-9), were blocked. Using genetically altered mice that did not have MMP-9, Dr. Sellati conducted some experiments. It turned out that when the MMP-9-deficient mice were exposed to a “lethal” dose of F. tularensis, compared to normal mice, only half the expected number of neutrophils entered the lungs and correspondingly, half the mice survived the infection. In the normal population of mice, none survived their respiratory tularemia.

“This had never been shown before,” says Dr. Sellati. “By reducing the immune response, we actually were able to cure half of the mice.”

Dr. Sellati says this exciting finding was published last year in The Journal of Immunology. However, a roadblock remained. “In the past, it’s been very hard to come up with a way to target MMP-9 to alter human immune response similar to the way it is altered in MMP-9-deficient mice,” he says. He wondered if there was perhaps another way of reducing the amount of neutrophils, which was really the goal, no matter the route. That’s when he came upon a researcher in Alabama, J. Edwin Blalock, Ph.D., who will conduct human trials giving patients with an inflammatory condition called chronic obstructive pulmonary disease (COPD) infusions of a “small molecule antagonist.” The drug appeared highly effective in reducing inflammation by limiting the number of neutrophils in the lungs of test animals of COPD.

“I gave him a call and asked him if he’d like to test these small molecule antagonists in an infectious disease model. He came right on board,” says Dr. Sellati, who says that if small molecule antagonists have the same effect in mice, they have much more potential of actually making the jump from animal to human trials.

“If it works, and remember, we’re still at the basic science stage with this, I’d envision small molecule antagonists being used perhaps as a nasal mist like antihistamine medications along with an antibiotic for maximum effect in keeping the lungs safe from inflammation and ridding the disease,” Dr. Sellati says.

The grant will cover four years of work, and in addition to testing small molecule antagonists to treat tularemia, the researchers also will examine their effectiveness in treating human plague and inhalational anthrax.

Albany Medical Center, a not-for-profit institution, is northeastern New York’s only academic health sciences center. The institution consists of Albany Medical Center Hospital, one of New York’s largest teaching hospitals; Albany Medical College, one of the nation’s oldest medical schools; and the Albany Medical Center Foundation, Inc., one of the region’s most active fundraising organizations.
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