Protecting cells from out-of-control immune reactions comes at a price: the same protein that quiets B and T cells to prevent autoimmune responses may also hinder the body’s fight against pathogens. Now researchers have found that in the case of the fungus Candida albicans, blocking an inhibitor protein known as CBLB offers a new way to clear systemic and skin fungal infections. The work appeared online July 18 in two studies published in Nature Medicine (1, 2) and one in The Journal of Experimental Medicine (3). The studies point to a novel drug development strategy for fungal infections, which affect nearly 1.5 million Americans annually and can prove fatal for immunocompromised individuals.
CBLB is known to tamp down the adaptive immune response, that portion of the immune system that is “trained” by exposure to a specific pathogen (the principle behind vaccination). However, two groups, working independently, discovered that CBLB can also block one class of receptors on innate immune cells. The result: a weak response to fungal infections. “This is really the first inhibitor of this receptor family, certainly in these [specific] pathways, so in that sense it’s quite a unique and novel finding,” says immunologist Sarah Gaffen of the University of Pittsburgh, who was not involved in the study.
Normally, the CBLB protein binds to surface receptors on T cells and tags them with ubiquitin, a small protein that marks the receptors as waste. Without these surface markers, T cells remain in check, stymieing uncontrolled auto-immune reactions.
But CBLB’s role in regulating the innate immune response to fungi was a mystery. Jian Zhang of Ohio State University in Columbus and his colleagues discovered that when they treated mouse cells with a fungal cell wall chemical named zymosan, as well as with other inflammatory stimuli, cells lacking the CBLB gene—and thus its restraining actions—produced a more intense inflammatory response to the fungal molecule than normal cells. In animals, this stronger reaction was better able to attack infecting fungi.
In a series of experiments, they found that CBLB works by binding to dectin-1 and dectin-2, two receptors known to recognize fungal cell wall proteins and recruit an enzyme named SYK, which initiates an inflammatory cascade to target fungal pathogens. CBLB attached ubiquitin tags to specific sites on dectin-1 and 2 and marked them for destruction, reducing inflammation and preventing immune cells from attacking the fungi.
“We found that in fungal infections, this intense host response which is usually blocked by CBLB is actually necessary,” Zhang said.
Karl Kuchler of the Medical University of Vienna, Josef Penninger of the Austrian Academy of Sciences and their colleagues also found that mice lacking CBLB could better defend against Candida infections because their immune cells—unhindered by CBLB—could produce a stronger inflammatory response via the actions of dectin-1, dectin-2, and the SYK protein. The team fused the CBLB-binding region of SYK with a Drosophila protein that can enter cells to form a cell-penetrating peptide that blocks CBLB activity. This little protein had no effect on mutant mice that already lacked the CBLB gene. But in control animals, the peptide protected the animals from systemic Candida infections.
“There have been very few examples that show how interfering with an overactive immune response can be beneficial for fungal infections,” says Kuchler. “Our results show that to eradicate fungi you don’t need to attack the pathogen. Modulating host responses can also be effective.”
Independently, a third group of researchers discovered that CBLB can regulate dectin-2 as well as a third receptor, dectin-3, via a similar SYK-mediated pathway, so mice lacking the protein were more resistant to fungal infections than control animals.
The new insights could lead to more effective drugs. “From a drug development point of view, it’s a lot easier to turn a pathway off than to switch it on,” Gaffen says. “In this case, having an inhibitor of an inhibitor is feasible, and that could have therapeutic uses.”