Very high magnification micrograph of coccidioidomycosis, also known as valley fever and California disease. GMS stain.
Image Credit: Nephron
(CC BY-SA 3.0)
Scientific Frontline: Extended "At a Glance" Summary: Valley Fever Immune Modulation
The Core Concept: Valley Fever (Coccidioidomycosis) is a severe dust-borne fungal infection, and recent studies reveal that life-threatening, disseminated cases can be successfully treated by modulating the patient's immune system.
Key Distinction/Mechanism: Unlike traditional treatments that attack the fungus directly with antifungal drugs, this approach corrects an abnormal immune response by either reversing T cell exhaustion or realigning a misdirected "Type 2" allergic immune reaction.
Major Frameworks/Components:
- T Cell Exhaustion: A weakened immune state where cells burn out from constant fungal exposure, marked by elevated levels of the PD-1 protein acting as a "brake" on the immune system.
- Type 2 Immune Skewing: An abnormal physiological response, found almost exclusively in males, where the body mistakenly interprets the fungal infection as an allergy or parasite.
- Therapeutic Modulation: The use of targeted medications—such as interferon gamma to reinvigorate T cells or the allergy drug dupilumab to reverse Type 2 skewing—to retune the body's natural defenses.
Branch of Science: Immunology, Microbiology, and Medical Genetics.
Future Application: Funding large-scale clinical trials to establish standardized dosing protocols for immune modulators, as well as deepening genetic research to understand underlying vulnerabilities in specific populations.
Why It Matters: Valley Fever is a proliferating and costly disease (costing California $1 billion annually). This immunological approach has demonstrated striking clinical success, restoring mobility and saving patients from life-threatening illness when conventional antifungal therapies proved ineffective.
Valley fever, technically known as coccidioidomycosis, is a dust-borne fungal infection that occurs in dry regions like the southwestern United States and is proliferating in California and Arizona. California alone spends $1 billion annually on treatment.
Valley fever starts in the lungs, but on rare occasions, it can spread to other parts of the body, including the brain. It can be life-threatening, and even when it clears, it can leave the patient debilitated for years afterward. To combat this infection, physicians have long relied on antifungal drugs. However, these medications do not always work when the infection has spread extensively. Seeking to better understand why the infection spreads in some individuals, UCLA researchers discovered that patients with severe illness exhibited an abnormal immune response. In some cases, the immune system was overactive; in other cases, it was underactive. These findings have opened new doors to treatment through immune system modulation.
“We've discovered two of the underlying immune programs that lead people to develop life-threatening disseminated Valley fever instead of just containing the infection in the lungs and fighting it off,” said Dr. Manish Butte, the E. Richard Stiehm Endowed Chair and professor of pediatrics at the David Geffen School of Medicine at UCLA, who led the team. “Moreover, we've discovered a new paradigm for treating these infections: we administer medications to modulate the immune system to fight the infections better.”
Dr. Butte holds joint appointments in the Departments of Microbiology, Immunology, and Molecular Genetics, and of Human Genetics.
In two recent studies published in the peer-reviewed journal JCI Insight, the team delved into why some people's immune systems are unable to effectively combat the infection.
In one study, the researchers examined the role of T cell exhaustion, a state in which immune cells burn out from constant exposure to a fungal antigen. They found that patients whose Valley fever disseminates had significantly weaker T cell responses early in the disease. Only 8% had detectable responses, compared with 44% of patients whose disease was mild. Their T cells showed elevated levels of a protein called PD-1, which acts as a "brake" on immune cells. This pattern of weak responses and elevated PD-1 expression is the classic hallmark of exhausted T cells. T cell exhaustion is commonly observed when T cells fight cancers, and many oncologists currently employ treatments to reverse the exhausted state and more effectively fight tumors. Inspired by the successes of oncologists, Dr. Butte’s team applied the same concept to Valley fever. The researchers found that blocking PD-1 essentially reinvigorated the T cells, causing them to produce interferon-gamma, which signals the immune system to more effectively fight the fungal infection.
The second study focuses on a different pattern of immune dysregulation that contributes to severe, disseminated Valley fever. Here, the researchers showed that approximately 25% of patients have an immune system abnormally skewed toward a "type 2" response—an immune program in which the body misinterprets Valley fever as an allergy or a parasite rather than a fungus. Curiously, this type 2 response was observed almost exclusively in males. In collaboration with Dr. Valerie Arboleda, an associate professor of pathology at UCLA, the team investigated the genetic links explaining why some individuals develop this type 2 response. They identified a set of rare genetic variants that explain the skewed responses in a subset of patients; however, the genetic basis for most individuals remained unsolved. Finally, they discovered that the allergy drug dupilumab, which blocks overactive allergic immunity, reversed this skewing in the laboratory.
Moving beyond the bench to the clinic, the team has begun applying these discoveries to the sickest Valley fever patients referred to UCLA. In a paper published in March, the team described treating 18 severe cases with interferon-gamma to boost the immune system. They also treated 14 severe cases exhibiting type 2 skewing with dupilumab, which recalibrated the patients' immune responses to better fight the fungus.
“The improvement patients had with our immune treatments was stunning. Patients who were sick and dying are now living their lives,” said Dr. Butte, who is also chief of the Department of Pediatrics’ Division of Immunology, Allergy, and Rheumatology.
For instance, one patient who was wheelchair-bound is walking again. Another, who had been on antifungal medications for several years and would easily become out of breath, is now able to run.
The next step is to obtain funding for clinical trials to further establish efficacy, determine who benefits, and learn more about treatment length and dosing to strengthen treatments against Valley fever, Dr. Butte said. He also aims to expand the search for the genetic underpinnings of dissemination and to explain why males are more likely to become severely ill.
Published in journal: JCI Insight (Both)
Title:
- Exhausted T cell phenotypes in disseminated coccidioidomycosis
- Th2 skewing in patients with disseminated coccidioidomycosis
Authors:
- Gregory D. Whitehill, Alexis V. Stephens, Timothy J. Thauland, Miguel A. Moreno Lastre, Matthew M. Tate, Sinem Beyhan, Royce H. Johnson, George R. Thompson III, Maria Garcia-Lloret, and Manish J. Butte
- Timothy J. Thauland, Smriti S. Nagarajan, Alexis V. Stephens, Samantha L. Jensen, Anviksha Srivastava, Miguel A. Moreno Lastre, Terrie S. Ahn, Chantana Bun, Michael T. Trump, Royce H. Johnson, George R. Thompson III, Maria I. Garcia-Lloret, Valerie A. Arboleda, Manish J. Butte
Source/Credit: University of California, Los Angeles / Health
Edited by: Scientific Frontline
Reference Number: imgy052726_01
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