Why does our immune system easily identify many bacterial and viral infections yet sometimes miss other invaders, such as pathogenic fungi? This question has troubled biologists for decades.
Now, Whitehead Institute and MIT researchers have discovered a biological "cloaking device" that may help pathogenic fungi hide from the immune system. When this network of genes is disabled, these virulent fungal invaders are suddenly rendered vulnerable to the body's defenses.
"This network may very well be one more tactic in the ongoing hide-and-seek game between our immune systems and pathogenic fungi," says Gerald Fink, lead author of the paper, a member of the Whitehead and an MIT professor of biology. The work appeared in a recent issue of the journal PLoS Pathogens.
Pathogenic fungi are the fastest-growing cause of hospital-acquired infections, preying mostly on patients with a compromised immune system. Chemotherapy, organ transplantation and HIV/AIDS are a few of the conditions that increase a patient's vulnerability.
Researchers have known for many years that the membranes of these fungal cells appear to be surrounded by an outer shell, almost like an M&M. The inside of the shell is marked by deposits of sugar called beta-glucan, molecules that are easily spotted by the immune system. The outer surface of the shell is composed primarily of a protein called mannan, which the immune system can't see. While this sort of outer shell is unique to fungal cells, no scientist had yet demonstrated what sort of biological role it might play.
Robert Wheeler, a postdoctoral scientist in the Fink lab, conducted experiments in which he placed fungal cells in a dish and introduced an antibody designed to detect the beta-glucan on the underside of the shell. However, in these experiments, the antibody often seemed to have trouble recognizing the beta-glucan, and, as a result, could not detect the fungal cell.
"We decided that we needed a way to test if the outer layer, the one made of mannan, might somehow be protecting beta-glucan from the immune system," says Wheeler.
Since many species of fungus, including baker's yeast, contain this mannan layer, Wheeler decided to use this common household product as a model for determining mannan's function.
After screening thousands of mutant yeast strains, Wheeler discovered a network of genes responsible for creating the mannan layer, genes that all had counterparts in pathogenic fungi. When Wheeler knocked out key genes in the mannan network in pathogenic fungi and placed them in a dish containing beta-glucan antibodies, the antibodies immediately "recognized" the fungi.
Next, Wheeler placed these fungal cells in a dish with certain immune system cells. With mannan disabled, the immune cells recognized the fungi far more efficiently. In an organism, that reaction would produce a full immune response.
"This mannan layer seems to be masking beta-glucan from the immune system," says Wheeler.
"Interactions between the immune system and pathogens are highly complex," says Fink. "On the surface, it looks like a 'point, counter-point' competition. One side evolves a particular defense, and then, through natural selection, the other side develops a way to counter that defense. This outer layer of mannan is one of many processes that pathogenic fungi have evolved to survive in what would otherwise be a hostile environment."
"No doubt these findings are certainly of interest to companies developing anti-fungal therapeutics," adds Fink. In particular, using a drug to disable the mannan layer and then allowing the immune system to naturally attack the fungi may prove a powerful new approach.
This research was supported by the Bushrod H. Campbell and Adah F. Hall Charity Fund, and by the National Institutes of Health.
