"We are in the midst of a revolution in the way researchers study infectious disease. Instead of depending on culture dishes as the only way to observe the behavior of pathogens, scientists are able to eavesdrop on the cross talk between invading microbes and the immune cells of our body," said Professor of Biology Richard Young. His lab has done this by using DNA microarrays to explore the responses of human macrophages to a variety of bacteria, and as a result, has found clues to making safer, more potent vaccines.
Macrophages--immune cells that are part of the first line of defense--recognize and engulf microbes in a vigilant effort to keep the body healthy. The researchers found that macrophages respond to a broad range of bacteria by sending off an alarm to the rest of the immune system and transforming into cells primed to mount an immune response.
Further study revealed that the macrophage didn't have to "see" the whole bacterium to send off its alarm signal, but the presence of specific bacterial components, such as proteins and sugars, induced activation. "These findings will help researchers design therapeutics that will stimulate the immune system in a targeted manner, perhaps with fewer side effects," said Young, lead author on the study, which appeared in the Feb. 5 issue of Proceedings of the National Academy of Sciences. Young is a member of the Whitehead Institute for Biomedical Research.
"The interplay between a person's immune system and a microbe's attempts to circumvent these defenses represents a complex relationship," said Gerard Nau, a first co-author on the study and a researcher in the Young lab. "DNA arrays help researchers dissect this struggle by measuring the activity of many genes in the immune cells as they respond to pathogens. As a result, researchers gain invaluable information about the strengths and vulnerabilities of the microbes and our own immune mechanisms during an infection." Ann Schlesinger, postdoctoral fellow in the Young lab, and Joan Richmond, a former Young lab member, were also first authors on the paper.
DNA-array studies improve our understanding of macrophage defenses, provide insights into disease development and suggest targets for therapeutic intervention. The researchers found, for instance, that Mycobacterium tuberculosis, the bacterium that causes tuberculosis, fail to activate critical macrophage genes that are involved in fighting bacteria. These bacteria are unique in that they can somehow survive inside the macrophage, only later to escape and cause disease.
It turns out that M. tuberculosis doesn't trigger the macrophage response to produce IL-12 and IL-15 (small, secreted proteins called cytokines) as other bacteria do. IL-12 plays a fundamental role in activating another arm of the immune system called T-helper responses, and is critical for host resistance to tuberculosis infection in mice and humans. The lack of strong IL-12 response in macrophages indicates that this may be one way that M. tuberculosis evades host defenses and supports the use of both IL-12 and IL-15 in clinical tuberculosis therapies, as suggested by animal models.
MACROPHAGE ACTIVATION
The researchers also found some specifics about the shared macrophage activation program, which was induced by a wide range of bacteria, including gram-positive, gram-negative and mycobacteria. While the activation program seemed to trigger a generic alarm that called on other antibacterial defenses of the immune system, the majority of changes triggered in the macrophage involved cell surface proteins and signaling molecules. Such changes generate new functions in the macrophage, suggesting a maturation process similar to that observed with other immune cells.
Interestingly, the presence of certain bacterial components was enough to activate the alarm signal. This suggests promising new adjuvants (compounds that make a vaccine more potent by increasing an immune response) that could be used in vaccine development. The list includes heat shock proteins, which supports their use in preclinical and clinical vaccine trials.
The bacterial components that set off the alarm signal activated a family of proteins called Toll-like receptors, suggesting that small molecule drugs designed to activate this receptor may provide a new therapeutic approach.
"DNA microarray data is providing us with unprecedented details about our own immune defense cells as they orchestrate a response to attacking bacterial pathogens that are responsible for some of the major diseases of mankind," said Young. "This information should lead to new therapeutic strategies against these diseases."
This work was supported by funds from NIH, Corning Inc., Affymetrix Inc., Millennium Pharmaceuticals Inc. and Bristol-Myers Squibb Co.
A version of this article appeared in MIT Tech Talk on February 6, 2002.
