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NIH Awards OHSU $4 Million Biodefense Contract to Study Tuberculosis

   Portland, Ore.

Researchers will look for cellular markers that could play important role in vaccine development.

Oregon Health & Science University's research team is one of only 14 teams around the country that will help the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, look for proteins that activate the body's immune response to emerging infectious diseases.

OHSU's team will focus on tuberculosis and will use cells from TB patients whose immune response has been successful at keeping the disease under control. The goal is to use this information to help create TB vaccines that can provide the same protection to others.

More than 2 million people die worldwide every year of TB, according to the World Health Organization. TB is caused by a bacteria, Mycobacterium tuberculosis, that usually attacks the lungs. The disease is spread through the air when people with active TB cough. Upon breathing in TB bacteria, the bacteria can settle in the lungs and begin to grow or move through the blood to other parts of the body, such as the kidney, spine and brain.

The Large-Scale Antibody and T Cell Epitope Discovery Program is a five-year, $4 million NIAID contract. It is the largest biodefense contract OHSU has received. OHSU's husband-and-wife physician research team, David and Deborah Lewinsohn, will lead the university's contract. David is a pulmonologist and immunologist at OHSU and the Portland Veterans Affairs Medical Center, while Deborah is a pediatric infectious disease specialist and immunologist at OHSU and Doernbecher Children's Hospital.

"TB remains one of the leading causes of infectious disease mortality worldwide, and we are excited to have the opportunity to participate in the effort to develop an improved TB vaccine," said David Lewinsohn.

The NIAID classifies multiple-drug-resistant TB as a category C bioterrorism agent because it is highly contagious, easily released in the air and can have 50 percent to 90 percent mortality rate. Whether TB is drug resistant doesn't matter to vaccine development, so the team will work with the less-dangerous and readily treatable form of the bacteria to find the cell markers, epitopes and antigens that tell the body when a bacteria has invaded cells and needs to be attacked.

The Lewinsohn team is using healthy people who are latently infected with TB as a model of the type of immune response they want to mimic in a vaccine. These individuals are infected with the disease, but don't show any signs or symptoms and are not contagious. The team will specifically use these person's CD8+ T cells. These immune response cells are designed to recognize a marker or epitope on the surface of an infected cell and activate the body's defense system.

The contract will proceed in three phases: First, the team will find the antigens, or proteins, in the infected cell created by TB using proteomics and genomics techniques. Then they will identify the smaller parts of those antigens, the epitopes, that the CD8+ cells need to recognize to activate the body's immune response against the bacteria.

The NIAID is creating a central public database of T cell and B cell - another form of immune response cell - antigens and epitopes that researchers can access when working on vaccine development.

"This database will help us speed up vaccine development," said David Lewinsohn.

The third step will be to take this information to Uganda, where millions of Africans are infected with TB, to see if patients' immune response, specifically CD8+ T cells, recognize the same antigens identified by the Lewinsohn research team.

One reason the NIAID awarded OHSU's team with this contract is its research strength with CD8+ cells. David Lewinsohn's laboratory is one of the few labs that has been successful at isolating and cloning CD8+ cells from people with latent TB. These clones will be used to help the team identify the antigens and epitopes.

"From an immunologist's standpoint, TB is a really challenging disease to work on because we need to understand how the cellular system works in order to create better vaccines," David Lewinsohn said.

In addition, the Lewinsohns have created a strong, integrated team of researchers from OHSU and subcontractors from University of Washington, Colorado State University and Case Western Reserve University.

Vaccines are usually designed to create an immune response using antibodies in the body that protect it from invading bacteria and viruses. But TB invades cells in a way that requires the body to battle the disease using T cells that can attack the cells and prompt a full immune response.

The Lewinsohn research team hopes its identification of TB antigens and epitopes will aid in its own vaccine development.

"It supports our scientific mission. The information we will gain from these studies will fuel new ideas, new projects, and give us reagents to pursue those projects.," said Deborah Lewinsohn.

David Lewinsohn, M.D., Ph.D., associate professor of medicine (pulmonary and critical care) and molecular microbiology and immunology in the OHSU School of Medicine and pulmonary and critical care medicine physician at the Portland Veterans Affair Medical Center.

Deborah Lewinsohn, M.D., Ph.D., associate professor of pediatrics and molecular microbiology and immunology in the OHSU School of Medicine and the chief of pediatric infectious diseases at Doernbecher Children's Hospital.


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