The Hoskins and Hull Labs are joining forces in the fight against life-threatening fungal infections common among leukemia and lymphoma patients thanks to funding from the Badger Challenge Award.
The Badger Challenge, an annual fundraising race held each fall, was established in 2016 to support ground-breaking investigations in cancer research at UW–Madison. All proceeds raised through the race fund cancer research initiatives, giving members of the broader Madison community who participate in the fundraiser an opportunity to support new and innovative lines of inquiry.
Among the 2022 awardees are biochemistry professor Aaron Hoskins and biomolecular chemistry professor Christina Hull. The award will support two doctoral students, Sierra Love (Hoskins Lab) and Megan McKeon (Hull Lab), both of whom are in their fifth year in the Genetics graduate program.
Their collaborative research will explore potential new treatments for fungal infection by uniting two labs with seemingly unrelated approaches. The Hoskins Lab’s work typically focuses on pre-mRNA splicing — an essential step in gene expression in all eukaryotes — and its relationship with human diseases. The Hull Lab works on identifying mechanisms for germination and growth of invasive human fungal pathogens.
But the collaboration was a natural fit.
“My lab was initially looking for things that could treat human cancers and the Hull Lab was looking for things that can be directly used as antifungal drugs,” says Hoskins. “Research in both of our labs was approaching the same question — is RNA splicing is a good target for antifungal therapy?”
Like bacteria and viruses, fungal spores are all around us. While it is rare for a healthy person to become sick from breathing fungal spores, in people who are immunocompromised (such as patients undergoing chemotherapy), some fungal spores can cause serious, and potentially fatal, infection. Cancer patients are often given prophylactic antifungal treatments to prevent such infections, but these treatments can come at a cost. Many of the antifungal treatments used today pose their own toxicity to humans, and long-term treatment can result in fungi developing drug-resistant mutations.
The Hoskins and Hull collaboration is exploring possibilities for more effective and less toxic antifungal treatments using RNA splicing inhibitors.
“Treating fatal fungal diseases in patients is challenging, and 50% of patients don’t survive invasive infections. That is a terrible statistic that we are hoping to change using new and creative approaches,” says Hull.
When RNA splicing is inhibited or otherwise goes awry, it can result in cell death or illness in the impacted organism. This can be exploited for medical treatment, as splicing inhibitors can be used to target specific pathogens. Preliminary research out of the Hoskins and Hull Labs suggests that splicing inhibitors can inhibit germination and growth in Cryptococcus — a fungus that causes fatal meningitis in humans — and that splicing inhibitors may also work in concert with current antifungal drugs to further protect from infection.
The new research, as part of the Badger Challenge award, will build off these findings to examine how multiple pathogenic fungi respond to splicing inhibitors alone and with the aid of antifungal drugs. “Fungal pathogens are an increasing risk, not only to immunocompromised people, but also to healthy ones,” says Hull. “This project promises to provide critically needed treatment options for cancer patients and identify antifungal agents for broader use as fungal infection rates continue to rise worldwide.”
The complementary skillsets and knowledge that Love and McKeon have developed at UW–Madison are essential to this research.
“My research looks at how fungal spores are formed, how they mature, and how they germinate,” says McKeon. “Cryptococcus is an environmental yeast that we have developed as a model for spore studies. We can now cultivate the fungus, set up crosses and isolate spores, and test compounds for antifungal activity — all through protocols developed in our lab.”
Love, on the other hand, has been studying RNA splicing inhibition with the nonpathogenic fungus, Saccharomyces, more commonly known as Baker’s yeast because it catalyzes the fermentation process that allows bread dough to rise.
“We’re utilizing yeast as a model to figure out what’s going on and to look for new drugs that can treat these kinds of diseases,” explains Love. “My role in this project will be doing a bunch of drug screenings” to learn more about how Crytpococcus growth and proliferation respond to a combination of splicing inhibitors and known therapeutic antifungal drugs.
Their partnership is a product of opportunities they’ve had to explore interdisciplinary approaches to scientific inquiry. “My thesis committee is made up of people from a lot of different scientific backgrounds,” says McKeon, “and their different perspectives have really helped me to develop my research.”
In graduate school, Love has focused on expanding her knowledge base and broadening her skills. “The programs — the communities — are very inclusive and provide a lot of opportunities for collaboration and professional development,” adds Love. “That’s really what science is about. Nothing happens in a vacuum.”
The Badger Challenge Award also provides Love, McKeon, and their research advisors with an opportunity to build on their skills and try something new.
“It’s definitely a new direction for us,” says Hoskins. “We’ve been thinking of inhibitors of RNA splicing for a while now, but the antifungal approach is something that I never thought about before we started getting the data in, and it’s something my lab wasn’t funded to do, either. The Badger Challenge Award gives us the funding to explore this and see where it goes.”
“The Badger Challenge Award has been fundamental in starting up a collaboration that we never expected in the first place,” says Love. “Getting projects like this off the ground can have a big impact if you’re given the opportunity to see where it can go.”
Written by Renata Solan. Photo: Paul Escalante/Department of Biochemistry.