Published On March 16, 2017
TUBERCULOSIS CONTINUES TO BE A LEADING CAUSE OF DEATH WORLDWIDE, and a third of the world’s population now harbors the bacterium that causes the disease. But while the search for a cheap and effective vaccine has been going on for more than 100 years, the one most widely used today is still only partially effective in children and adults.
A team from the Ragon Institute in Boston may have a lead on how tuberculosis vaccines could work better. And their new line of attack, which looks at a different way to manipulate the immune system, may not only help to identify and treat the disease, but open an innovative line of thinking about other intractable diseases, too.
Their approach looks at the role played by antibodies. The body’s immune response to most infections happens along two main avenues: On one, T cells scout the body for pathogens and infected cells, and destroy them; the other involves antibodies, complex proteins hundreds of times smaller than T cells, that lock onto the invaders and neutralize them, or signal for help from other cells.
“Until now, tuberculosis research has focused almost exclusively on immunity based on T cells,” says Sarah Fortune, director of the Tuberculosis Program at the Ragon Institute. “We weren’t looking at antibodies.”
But Ragon researcher Galit Alter and colleagues have recently developed tools that can analyze the tiny antibodies in greater resolution. Alter and Fortune looked at the ones that the body produces when it is infected with tuberculosis. They discovered that these proteins were very different in people who were able to control their infection—people who carried a latent form of the disease—than in those who developed active symptoms. The difference was in the sugar “decorations” on the tail of the proteins, which turn out to correlate to their ability to kill bacteria in a variety of different ways.
Shaped like the letter Y, an antibody has heads that recognize a pathogen and lock onto it. The role of the “tail” at the bottom of the Y has been less well studied, though researchers know that it typically signals and recruits other immune cells to assist in controlling infection. Alter and Fortune were able to show that people with a latent, controlled form of tuberculosis had antibodies with tails that were better at recruiting natural killer cells, the body’s deadliest immune cells. In contrast, the patients with active disease had antibodies that trigger inflammation, Alter says.
Alter teased out the data with a combination of biophysical and cellular assays and computational tools to map out complex interactions in human blood. Although it isn’t clear why the sugar decorations on the antibodies’ tails differ, her results showed that individuals who were able to control the infection had different patterns from those who couldn’t.
“What’s exciting is that nobody ever thought that antibodies were important or relevant in TB control,” says Alter. “It had been dismissed since Robert Koch discovered TB more than 100 years ago.”
Fortune and Alter, who published their results in Cell last September, believe it might be possible to develop therapies that use what they’ve learned—creating monoclonal antibodies, a fast-growing class of drugs that can flag a more effective immune response against TB, and giving them to patients. That could potentially replace current treatments, which involve six to nine months of antibiotics.
The finding also could help in developing a vaccine, which works by stimulating an effective immune response. “It is worth figuring out in much more detail what the antibody heads should recognize, and what the tail should look like,” says Fortune. “That will help vaccine developers generate an antibody response, which is an easier path than trying to develop a T-cell based vaccine.”
Their discovery about antibody tails may have diagnostic applications as well. A current skin test or blood tests can detect a person’s exposure to TB, but aren’t very good at differentiating between latent and active TB disease. Because only patients with active TB can transmit the disease, being able to identify them could help clinicians prioritize their treatment.
Most important, the findings could guide similar research into other tricky diseases. TB is not the only pathogen that causes latent infection that sometimes reactivates, says Fortune. Malaria, hepatitis C and HIV all are global killers that have latent and active states, and all of them have resisted vaccine developers’ efforts thus far. “In these diseases, protective immune responses are working through unprecedented or unorthodox ways,” explains Alter. Catching their antibodies by the tail may offer new promise for diagnosing and treating these diseases as well.
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