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Sunday, January 23, 2022

18 fungal proteins found to play role in spore formation

“We study sex in an obscure fungus,” says Dr. Christina Hull, an associate professor in UW-Madison’s biomolecular chemistry department.

This statement might cause some head-scratching upon first impression. The word “fungus” might come to mind as the mushrooms everyone picks off of their pizzas, or perhaps as something a little more annoying like athlete’s foot. In reality, Dr. Hull’s studies of fungal sex are huge breakthroughs in the understanding of serious fungal diseases like fungal meningitis.

Fungi infect humans through their spores, which are what fungi produce when they have sex. The spores enter a person’s body and germinate into yeast, and the yeast is what causes the disease. Serious fungal diseases can have a shocking mortality rate of 50% in humans, and there is no effective way of treating such infections.

“There are some huge challenges [with treating fungal diseases],” says Hull, “because fungi are eukaryotes, human are eukaryotes, if you try and kill a fungus that’s in a human, you often kill the human.”

“Severe fungal disease is very difficult to treat and people die from severe fungal diseases, so I’m really interested in how the basic biology of fungi [can] inform better treatments.”

To understand fungal diseases, Hull and her lab study the fungus Cryptococcus neoformans, which causes fungal meningitis in humans.

Their path started when graduate student Michael Botts discovered how to purify spores in large amounts, so that they were able to break the spores down to analyze their proteins and genes. Spores are unicellular reproductive bodies that eventually become new organisms.

Spore proteins help a spore function and germinate into disease-causing yeast. Specific genes control the proteins and if a gene activates production of proteins that are involved with yeast germination, then the infected person gets sick.

In collaboration with Dr. Joshua Coon’s lab in the chemistry department, Hull and her team were able to identify 18 proteins that were potentially involved in spore germination using cutting-edge technology.

Mingwei Huang, a graduate student in Hull’s lab, deleted or “knocked out” each gene that controlled one of the proteins and observed the function of the resulting mutated fungus.

If one of the mutants didn’t turn into yeast after a gene had been knocked out, then that particular gene was an important helper for turning a spore into yeast and making it infectious.

Eventually, Hull and her team were able to find a protein that was directly involved with the process. With that protein, they hope to further understand how spores turn into yeast and apply that to make a marketable drug that could stop fungal diseases.

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“One of the things we’re doing is looking for inhibitors of the germination process, so we’re in the process of doing a small molecule screen, screening tens of thousands of compounds for their ability to stop a spore,” says Hull, “Ultimately, all of those chemical tools could be germination inhibitors that you could give to patients.”

“If you were to develop one of these into a marketable drug, if germination is a process specific to spores that humans don’t do, then if you have a drug against that, it might not be toxic to people. If [a spore] can’t [germinate], then you’re not going to be able to grow, you’re not going to be able to make anybody sick,” Hull says.

Having a drug that could prevent fungal diseases in humans would be groundbreaking, especially for immunocompromised people such as HIV/AIDS patients who are at a higher risk for fungal diseases.

It is also incredibly important in organ transplants, since patients are given drugs that suppress their immune systems. If the patients are given these preventive drugs for fungal diseases after their immune systems are shut down, then the risk of them getting sick during the surgery is drastically minimized.

The core of Hull’s research at its simplest may just seem like watching fungi having sex, but the implications and conclusions drawn from those observations matter very much to us and our health. Having a treatment for fungal diseases would be visionary in every right.

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