Basic-Science Study Reveals How Fungi Hijack the Body's Immune System
Madison, Wisconsin - Researchers at the University of Wisconsin-Madison have uncovered a clever way fungi can hijack the body’s attempts to clear a fungal infection.
Enzymes produced by the fungus mimic cell signals that temper white blood-cell development, normally used by the body to manage inflammatory responses.
Detailed in the recent study published this week (Feb. 25) in Cell Host & Microbe, researchers were able to render this fungal strategy ineffective with a treatment of sitagliptin, a pharmaceutical enzyme inhibitor approved for treatment of type 2 diabetes.
While this research was conducted in vitro and in a mouse model, researchers at the UW School of Medicine and Public Health want to learn if this enzyme is present in human fungal infections as well. If so, this research could lead to a valuable weapon to fight such infections.
Fungal infections arise in people with compromised immune systems, organ or stem-cell recipients, cancer patients and those on medication that weakens the immune system. However, most fungal infections actually occur in previously healthy individuals that breathe in mold spores from the soil.
“Scientists interested in bone marrow and stem-cell transplantation, who were investigating ways to facilitate transplantation to get good establishment of transplanted marrow, noticed that if you interfere with [the mammalian enzyme] CD26 and block its ability to cleave the growth factor that stimulates stem cells to produce blood products important to the immune system, you got better establishment of the transplant” said Bruce Klein, professor of pediatrics and medical microbiology and immunology at UW-Madison.
Knowing that a close structural mimic of this enzyme is also made by this fungus left Klein and collaborators with the question: If the mammalian enzyme is cleaving, is the fungal enzyme doing that too?
The growth factor (granulocyte-macrophage colony-stimulating factor) nurtures the development of white blood cells both in and outside of the marrow. For instance, it enables their development from very early stages to fully differentiated white blood cells. It also promotes the differentiation of early-stage monocytes into dendritic cells, which are critical in adaptive immunity.
Once the body recognizes an invader, it produces antibodies and T cells to effectively create immunity against it. This is also the basis for how vaccines work.
But for an immune response to be effective, it also must be a measured response. An overactive immune response can cause over-inflammation and damage to tissues just as an infection might, so the body needs to temper that inflammation. Insert enzymes like CD26.
Through a variety of experiments, Klein and collaborators demonstrated that the fungal mimic was indeed acting like the human CD26 to stop an immune response before the body could mount an offensive. This early immune dysfunction allows the fungus to gain a foothold and make for a progressive infection. But there are ways to inhibit the body’s response to temper inflammation.
“We tried a chemical compound that has known inhibitory activity, and there's also an FDA-approved drug that's commonly used for the treatment of diabetes,” said Klein. “Both had the same effect in mice in significantly ameliorating the infection.”
Next steps for Klein include seeing if his team can detect evidence of this fungal enzyme in human patients. For instance, Klein would like to look at samples of lung secretions for pneumonia patients and see if the enzyme is present as they are in mice. If evidence is established, one could theoretically try the already FDA-approved drug in an off-label use.
What’s perhaps just as exciting as finding a way to fight fungal infections is that this enzyme produced by fungi is conserved across kingdoms of microbes like bacteria and parasites.
“There is some indirect evidence that it could promote infection with these other pathogens, so we'd like to see how widely this holds true in disease pathogenesis,” said Klein. “It’s speculative at this point, but there is some early evidence to follow.”
This work was supported by multiple National Institutes of Health grants and the American Heart Association. Related work was funded by the Wisconsin Partnership Program. The WPP represents a far-reaching commitment by the UW School of Medicine and Public Health to improve the health and well-being of Wisconsinites through investments in research, education and community partnerships.
Established in 2004, the Wisconsin Partnership Program has awarded more than 400 research, education and community partnership grants totaling more than $180 million aimed at improving the health of Wisconsin residents.
Date Published: 02/26/2016