To discover whether pathogens could be induced to mount such a defense in macrophages, the St. Jude team studied the arginase-inducing activity of the microorganisms that cause tuberculosis and toxoplasmosis, as well as a relative of tuberculosis, Mycobacterium bovis, that is used as a live vaccine.
Studies in macrophages in the culture dish and in mice demonstrated that these microbes did trigger arginase production and that this triggering suppressed nitric oxide production in macrophages. The researchers also traced the biochemical mechanism by which the organisms triggered arginasefinding that the microbes hijack the machinery by which the macrophages recognize invading pathogens.
Also working with mice, the researchers tested whether shutting down arginase might enhance the ability to battle tuberculosis. They found that mice genetically engineered to lack arginase only in their macrophages showed superior resistance to tuberculosis and toxoplasmosis.
"Our findings reveal that these pathogens have evolved to exploit a biological loophole in the immune system," Murray said. "This discovery offers two important insights. It reaffirms the notion that pathogens have an incredibly diverse way of manipulating their hosts. And it reveals a new pathway by which a pathogen can induce an enzyme that is normally not present in those macrophages and use the induction of that enzyme to its advantage."
Murray emphasized that the findings are basic, and that the researchers can only speculate about possible clinical implications at the moment. "However, we believe it could be possible to develop targeted drugs to specifically inhibit pathogens' ability to induce arginase in macrophages," he said. Such drugs might suppress such diseases as tuberculosis and toxoplasmosis by increasing the ability of macrophages to make nitric oxide. Researchers believe that the drugs could work in combination with
|Contact: Summer Freeman|
St. Jude Children's Research Hospital