What Is It Eating? A Researcher’s Six-Year Chase to Understand How a Deadly Mold Survives Inside Human Lungs

Every day, we breathe in spores of Aspergillus fumigatus without a second thought. The mold is everywhere - in soil, in compost, in the air of nearly every room we enter. For most people, the immune system clears it out before it ever becomes a problem. But for someone with a weakened immune system, those same spores can settle into the lung, wake up and begin to grow. Once that happens, the odds turn grim. Mortality rates for the resulting infection, invasive aspergillosis, can run as high as 90%.

Jarrod Fortwendel, PhD, has spent his career trying to understand what happens in that narrow window between a spore drifting into the lung and a full-blown, tissue-invading infection. A new five-year, $3.22 million R01 grant from the National Institute of Allergy and Infectious Diseases will let him and his team at the University of Tennessee Health Sciences College of Pharmacy dig deeper into a question that sounds almost simple: what is this organism eating, and can we stop it?

A Different Kind of Question

Dr. Fortwendel's studies of Aspergillus have been funded by six previous national grants. Much of his prior research focused on antifungal resistance and the way Aspergillus, like drug-resistant bacteria or viruses, can evolve to shrug off the medications used to treat it.

This project starts from a different place. "It's a question around pathogenic fitness," he said, "which, simply put, is trying to understand how a pathogen, a microbe like Aspergillus, can live inside of a human host and how it causes disease. What food does it eat while it's in there? How does it even know the food is there? How does it use that food to fuel tissue invasion?"

Like any living thing, Aspergillus needs fuel to grow. "Unfortunately for us as human hosts, it's usually parts of our tissues that it's using as food," Dr. Fortwendel said. "If we can understand those processes, maybe we can develop ways to stop the organism from doing that, as a new therapy."

The lung is where the story begins. Spores land there in a dormant, resting state. Before the fungus can do any damage, it has to break that dormancy by sensing food in its environment and germinating into long, invasive tubes called hyphae.

"We really don't have a good understanding of what Aspergillus uses as food in the host and how it even is going through that process of breaking dormancy," Dr. Fortwendel said.

Once that transformation happens in an immunocompromised patient and the organism spreads into tissue and the bloodstream, treatment becomes an uphill battle. This grant is aimed at that early, poorly understood window. By identifying the food source and the molecular machinery Aspergillus uses to sense it, "maybe we can block that process," Dr. Fortwendel said.

An Accidental Discovery, Six Years in the Making

The road to this grant started with a tool built for something else entirely. Years earlier, Dr. Fortwendel's lab had developed a faster method for editing the Aspergillus genome, a way to delete individual genes and then ask what job each one had been doing. That method let the team build an entire library of mutant strains, each missing a different gene.

Screening that library wasn't the point of the original grant that funded it. But once the strains existed, the lab started running them through tests anyway, looking for anything interesting, including whether the mutants could grow on lab media formulated to mimic the carbon sources found in human lung tissue.

One mutant stood out immediately. "This mutant, totally surprisingly - we didn't even know what the gene was that we had deleted - was completely unable to grow in the presence of carbon sources that are more present in our lung than what we would typically use in a laboratory to grow it," Dr. Fortwendel recalled. "That observation happened about six years ago."

It took years of follow-up work to figure out why. The gene in question encoded a protein the team came to call CotA. What the team found was not what they expected. A normal, "wild-type" strain of Aspergillus produces two versions of the CotA protein, similar in structure but different in size, and likely different in function. The mutant strain made only one of them.

"The fact that it made one at all was surprising to us," Dr. Fortwendel said. "The fact that our entire phenotype is driven by loss of one of those two is really, really interesting, because it shows that you have very specific functions of those two isoforms."

Understanding that single missing piece, he said, could be the key to unlocking how the fungus senses and uses sugar sources inside the host.

Built on a Foundation of Collaboration

Dr. Fortwendel traces his fascination with Aspergillus back to graduate school, long before this specific discovery. But he credits the environment at UT Health Sciences, specifically its mycology research community, with making the work possible.

"We have a very strong mycology group here," he said. "It's always great in science to be able to interact with people who do something completely different than you, so you get this interdisciplinary interaction and collaboration. But it's also really great to have people next to you and down the hall who speak the exact same language."

That kind of close, informed feedback has been essential to keeping the science moving forward. "When you share your science, or bring an idea of something you want to do to your colleagues, the feedback you get is critical and not just supportive," he said. "It actually helps to drive your work forward. A lot of it was born out of stuff that started 10 years ago, when I came here, of having people who are trained like you and think like you, speak directly into your science. I think that's a big part of the reason my success has been pretty stable. It's not just on the investigator; it's on the people you interact with."

The project extends beyond UT Health Sciences. Dr. Fortwendel is working with two external collaborators: John Panepinto, PhD, professor of microbiology and immunology at the University at Buffalo, and C. Joel McManus, PhD, associate professor of biological sciences at Carnegie Mellon University. Adela Martin Vicente Stamper, research associate at UT Health Sciences, has led the day-to-day work on the project for years and will continue driving it forward under the new funding.

What Comes Next

With the grant, Dr. Fortwendel's team will spend the next five years testing a hypothesis born from that six-year-old observation, that the two forms of the CotA protein are separately controlled and each play distinct roles in helping Aspergillus translate the presence of certain carbon sources into the kind of aggressive, invasive growth that makes the infection so dangerous.

It's slow, patient science, built on years of screening, follow-up and conversations with colleagues down the hall. If it works, it could point toward an entirely new class of antifungal targets, aimed not at killing the organism outright, but at cutting off its food supply before it ever gets the chance to invade.