A Colorado State University tuberculosis specialist, part of a multi-university research team, has evaluated a potential mechanism by which an innate immune response is triggered to kill tuberculosis cells in mice and in humans.
John Belisle, assistant professor of microbiology, and investigators from nine universities and laboratories in the United States, Europe and Japan describe their work in the Feb. 23 issue of Science. They analyze how a primitive immune response that could be hundreds of millions of years old helps people fight off tuberculosis.
Within the past few years, a relatively non-specific but effective immune receptor called a Toll protein was identified in common fruit flies. Insects and reptiles, without the biologic complexity to develop mammalian-type immune systems, needed something simple and effective to fight bacteria, and Toll proteins were it. Mammals later were found to have similar proteins, called Toll-like receptors, or TLRs.
TLRs project through the cell membrane of a phagocytic (bacteria-killing) cell, such as a macrophage. The external part is designed to match a variety of structures common to the bacteria’s cell walls and is called a receptor.
Humans "possess both very highly developed immune responses and very primitive immune responses," Belisle said. Unlike acquired immune systems (for example, antibodies or antigen specific lymphocytes created by vaccines against hepatitis, measles or other infectious diseases), TLRs act as a first line of defense to detect anything that’s "not-self." "TLRs simply say, ‘This is a bacterium. This is bad. We need to get rid of it,’" Belisle said. When the outside, receptor part encounters something "not self" – in this case a bacterial cell wall structure termed a lipoprotein – the TLR starts a chemical cascade inside the cell, instructing it to engulf and destroy the invader.
"What the TLRs see are a whole array of bacterial cell-membrane products," Belisle said. "Those products are fairly unique to bacteria, but they’re ubiquitous among many bacterial species."
Belisle, a member of the Mycobacteriology Laboratory at Colorado State that has carried out extensive research on TB, produced the purified bacterial lipoprotein for the current project, led by Robert Modlin of the University of California at Los Angeles’ School of Medicine. In an earlier project in which he played a larger role, Belisle and collaborators looked for a bacterial product that could stimulate production of an immune-system molecule called interleukin-12. They found the stimulator was a bacterial lipoprotein and the receptor for the lipoprotein was a TLR. The current work demonstrates that when macrophages are stimulated through the TLRs, they are primed to kill the bacterium that causes tuberculosis. Experiments on mice, which have immune systems remarkably similar to humans, and human immune cells raise an interesting question, Belisle said. Mouse macrophages, having identified and engulfed a TB cell, then secrete nitric oxide, which is toxic to the bacterium. Human macrophages also engulf a tuberculosis bacterium, but how they kill it remains unknown.
"(TLRs) are a primitive first line of immune defense, but all of this hopefully leads to an acquired response," perhaps involving other chemicals toxic to TB bacteria, Belisle said. He added that TB is a major global health problem and that the incidence of this dreaded disease is not subsiding, but also that relatively few people who are exposed go on to become ill from full-fledged TB.
From here, Belisle said, "We need to do two things. We need to understand the final pieces of the puzzle. What are the human macrophages producing when stimulated through the TLRs to kill the tuberculosis bacteria?
"And of all these TB infections, only a small percentage of people develop the disease. The rest seem to control the bacteria. How important are TLRs in controlling the initial infection?"