The Autoimmune Catch-22: When Fungal Infections Hide in Plain Sight
In the sun-baked soils of the American Southwest, the fungus Coccidioides lies dormant as microscopic, barrel-shaped spores. When a dust storm rips across the desert, or heavy machinery tears into a construction site, these spores launch into the air. A single breath is all it takes for one to bypass the body's defenses and settle deep in the lungs.
Once nestled in the warm, moist tissue, the spore transforms into a thick-walled spherule that duplicates its DNA over and over, producing hundreds of internal clones called endospores. Like an over-inflated balloon, the spherule eventually bursts, flooding the surrounding tissue with new spores - each one capable of repeating the destructive cycle.
So what does this have to do with autoimmune disease?
More than most people realize.
Over 6 million people die from fungal infections worldwide every year. Coccidioides (the cause of Valley Fever) is the dominant fungal threat in the western U.S. and is on pace to expand across half the country by 2040, putting a growing number of autoimmune patients directly in its path.
A personal fight. An underfunded threat.
"It's a massively underfunded field," says Dr. Adam Buntzman, PhD, who has spent years investigating Valley Fever at the BIO5 Institute at the University of Arizona. The gap in funding is personal for him: he survived Valley Fever himself as an autoimmune disease patient.
"It's very painful," he recalls. "I was in the hospital for ten days, and many other patients have had much more severe outcomes -- losing limbs, brain infections, and loss of life."
During a case of Valley fever patients describe a bone-crushing exhaustion that makes lifting their arms feel impossible. The immune response can also inflame the joints, causing swelling and stiffness in the ankles, knees, and wrists, earning the illness its old nickname, "desert rheumatism."
Today, Dr. Buntzman dedicates his career to helping high-risk autoimmune patients in the Southwest catch latent fungal infections early, before they begin immunosuppressive therapies.
"Many of our fungal disease patients also have an autoimmune disease," he explains. "You can see a thousand mutations in specific genes that contribute to the development of autoimmunity through a different path than in other patient populations. In those with severe fungal infections, you often see similar mutations to those observed in autoimmune patients and some mutations that would not have been identified in the general population. It's an opportunity to see the overlap between two diseases, and that overlap reveals the underlying novel mechanisms of both diseases."
With hundreds of new immunosuppressive drugs entering the market, Dr. Buntzman believes healthcare systems are unintentionally expanding the population vulnerable to fungal reactivation.
"The goal at Praespero is to uncover treatments that don't suppress the immune system at all, but instead target root causes," he says, noting the conventional approach is to blindly start treating patients with autoimmune therapies like TNF inhibitors, JAK-STAT inhibitors, or B-cell depletion drugs. If the patient’s fungal infection gets worse then the clinicians have to stop the autoimmune therapy altogether. An ideal alternative, Dr. Buntzman notes, would be to detect, treat, and clear fungal infections before starting the autoimmune therapy.
"It's a classic catch 22. Balancing immune suppression and infection control is one of the toughest challenges in oncology and autoimmunity."
Until better preventive or more targeted treatments exist, Dr. Buntzman's lab believes the answer is to give doctors a robust clinical toolbox: diagnostics to catch latent infections early, and therapeutics strong enough to clear them -- allowing autoimmune or cancer treatment to proceed safely. "We also need more precise therapeutics that reduce the level of immune suppression needed," he adds. "Then we can break the autoimmune/infection Catch-22 cycle."
"It's a classic catch 22. Balancing immune suppression and infection control is one of the toughest challenges in oncology and autoimmunity."
Mapping the immune system
A small step toward solving this Catch-22, involves giant leaps in immune mapping. This part of Praespero's partnership with Dr. Buntzman began years earlier, with an ambitious effort to decode the adaptive immune system. Working alongside engineers, his team set out to map the near-infinite landscape of immune receptors.
"The adaptive immune system is the most complex biological system we know to exist," Dr. Buntzman explains. "The number of ways you can recombine an immune receptor is astronomically large, 100 million times the number of stars in our Milky Way galaxy."
Using massive computer clusters spanning hundreds of thousands of CPUs was not effective, so the team achieved something remarkable: in just sixteen days, they mapped the entirety of the T-cell repertoire space using Graphical Processing Units (GPUs). "The developments that followed would have been impossible without Praespero's funding," he says.
Turning discovery into hope
That early success laid the groundwork for everything that followed. Praespero went on to fund projects tackling latent fungal infections in autoimmune patients, including development of a Valley Fever vaccine and a more precise diagnostic tool.
Dr. Buntzman believes the immune system mapping project became the foundation for major breakthroughs.
"This kind of project would have been unlikely to secure funding through a traditional grant framework," he notes. "Yet it's precisely the kind of insight that accelerates progress toward better treatments for autoimmune conditions."
More recently, Praespero supported Dr Buntzman as he helped produce a first-in-class fungal vaccine and a diagnostic test dozens of times more sensitive than the current clinical standard - both of which the team hopes to bring to patients. Praespero has also funded high-throughput screening of every FDA-approved drug, uncovering promising new antifungal candidates. Now, the organization is backing Dr. Buntzman's next frontier: precision antifungal cellular therapeutics.
"We hope that together, the diagnostic, the vaccine, the newly identified drugs, and the cellular therapeutics will combine to eliminate latent Valley Fever infections from the list of concerns for autoimmune patients," he says. "This would leave their doctors free to treat autoimmune patients without risk of infection."
In the meantime, Dr. Buntzman finds fuel in the small victories - testing compounds in the lab and watching them destroy the fungus.
"Those are the beautiful moments, watching a fungus die in a tube," he says. "It pushes me forward, because I want to do that in a person's body," says Dr. Buntzman. "What I just saw might actually save someone's grandma, or sister, or cousin, or child. That's the hope. It requires a lot of resources, and it's a long road - but it's those eureka moments that keep you going."
"Those are the beautiful moments, watching a fungus die in a tube. It pushes me forward, because I want to do that in a person's body. What I just saw might actually save someone's grandma, or sister, or cousin, or child."
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