UCLA researchers have cracked open a new pathway to treating Valley Fever, a dust-borne fungal infection that spreads silently through the lungs and, in severe cases, to the brain and beyond. The discovery centers on an elegant idea: stop battling the fungus itself, and instead repair the broken immune systems of the patients it infects.
Valley Fever, technically Coccidioidomycosis, has been proliferating across California and Arizona, where the dry climate creates ideal conditions for the fungus to spread through the air. California alone spends $1 billion annually treating the infection. While most people who inhale the fungus recover, some develop life-threatening disseminated disease—the kind that spreads beyond the lungs and can debilitate patients for years, even after the infection clears.
For decades, physicians relied on antifungal drugs to fight the disease. But these medications often fail when the infection has spread too extensively. Dr. Manish Butte, the E. Richard Stiehm Endowed Chair and Professor of Pediatrics at UCLA's David Geffen School of Medicine, and his team decided to investigate why some immune systems could contain the infection while others couldn't. What they found was striking: patients with severe illness didn't have a fungus problem alone—they had an immune problem.
In one set of patients, the problem was exhaustion. Butte's team discovered that people whose Valley Fever disseminated had significantly weaker T cell responses early in disease. Only 8% had detectable immune responses compared with 44% of patients with mild disease. These exhausted T cells displayed elevated levels of PD-1, a protein that acts as a biological brake on immune function. This pattern mirrors what happens in cancer patients—and that gave the researchers an idea. Oncologists have had remarkable success with drugs that block PD-1 to reinvigorate exhausted T cells. Butte's team tried the same approach for Valley Fever and found that blocking PD-1 essentially reactivated the immune system, causing T cells to produce interferon gamma, which signals the body to fight the fungal infection more effectively.
A second group of patients had a different problem: about 25% of severe cases, almost exclusively in males, had immune systems that were abnormally skewed toward a "Type 2" response—the same immune program the body uses to fight allergies and parasites rather than fungi. The fungus was being misinterpreted as an allergen. Collaborating with Dr. Valerie Arboleda, an associate professor of pathology at UCLA, the team traced some of these skewed responses to rare genetic variants, though most cases remained genetically unsolved. Crucially, they discovered that dupilumab, an allergy medication already approved and in use, could reverse the skewing in the laboratory.
Rather than waiting for perfect understanding, Butte's team moved directly into the clinic with their sickest patients. They treated 18 severe cases with interferon gamma to boost immune function and 14 severe cases with Type 2 skewing using dupilumab to reorient their immune response. The results, published in Clinical Infectious Diseases, demonstrated what Butte described as stunning improvement in patients who had been gravely ill.
Two peer-reviewed papers in JCI Insight detail the immunological mechanisms behind these findings. The paradigm shift is profound: instead of fighting the fungus harder, doctors are learning to fight it smarter by modulating the immune system itself.