Fighting TB Might be a Matter of 'Flipping a Switch" in Immune Response

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Scientists are focusing on a new concept in fighting airborne pathogens by manipulating what is called the “switching time,” the point at which a highly regulated immune response gives way to powerful cells that specialize in fighting a specific invading bug.

In the case of tuberculosis, Ohio State University researchers are using mathematical modeling to determine whether a change to the natural switching time would result in a more effective immune response. They also are analyzing which parts of the immune response are most important to striking a balance between properly timing the switch and completing the task at hand – killing the microbe.

The complex modeling takes into account the huge assortment of cells and molecules at work in the human immune response to Mycobacterium tuberculosis, the microbe that causes TB. The response to all airborne pathogens is particularly complicated because it takes place in the highly protective environment of the lung. Human lungs are programmed to minimize immune responses as a way to avoid inflammation, which could interfere with breathing.

The modeling suggests that the average switching time occurs about 50 days after tuberculosis invades the lung, which roughly coincides with clinical expectations that a skin test will turn up positive for TB between four and eight weeks after infection.

By that time, bacteria have settled in and are harder to kill, even with the more robust immune response. Because TB is highly evolved and adapted to the human host, the launch of the stronger immune response goes unnoticed in about 90 percent of infections.

With less adapted but virulent pathogens, on the other hand, an individual becomes acutely ill, and sometimes dies, when the switching time occurs. As the immune response kicks into high gear, toxic infection-fighting warrior cells cause what could be considered collateral damage by harming lung tissue at the same time that they kill the invading bugs.

The researchers say mathematical models that predict relationships and interactions in the immune response could guide planning for therapies that would be designed to either accelerate or slow the switching time, depending on the pathogen.

“A great problem in developing drugs and vaccines against airborne pathogens is this apparent bottleneck in the immune response and the inability to quickly and effectively eradicate microbes in the lung environment,” said Larry Schlesinger, professor of internal medicine and director of the division of infectious diseases at Ohio State and a senior author of the study. “Understanding that bottleneck is an important part of this paper, and brings new insight into how to override the problem with tuberculosis and other pathogens.”

The research is scheduled to appear in the online early edition of the Proceedings of the National Academy of Sciences.

About 2 billion people worldwide are thought to be infected with TB. People who are infected can harbor the bacterium without symptoms for decades, but an estimated one in 10 will develop active disease characterized by a chronic cough and chest pain. Both active and latent infections are treated with a combination of antibiotics that patients take for at least six months.

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