Valley Fever, technically known as Coccidioidomycosis, is a dust-borne fungal infection that occurs in dry regions like the southwestern US and is proliferating in California and Arizona. California alone spends $1 billion a year on treatment.
Valley Fever starts in the lungs, but in rare occasions can spread to other parts of the body, even to the brain. It can be life-threatening, and even when it clears can leave the patient debilitated for years afterward. To combat this infection, physicians have long relied on antifungal drugs. But they don't always work when the infection has spread too extensively. To better understand why the infection spreads in some individuals, UCLA researchers found that patients with severe illness had an abnormal immune response. In some cases, the immune system was overactive; in other cases it was underactive. These findings opened new doors to treatment by modulating the immune system.
"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 to treating these infections: we give medicines to modulate the immune system to fight the infections better."
Dr. Butte has joint appointments in the Depts. of Microbiology, Immunology, and Molecular Genetics and Human Genetics.
Now, in two studies published in the peer-reviewed JCI Insight, the team delves into why some peoples' immune systems are unable to effectively combat the infection.
In one , the researchers examined the role of T cell exhaustion, which is when 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 pattern seen in exhausted T cells. T cell exhaustion is commonly seen when T cells fight cancers, and many oncologists nowadays employ treatments to undo the exhausted state and fight cancers better. Inspired by the successes of oncologists, Dr. Butte's team tried the same idea in Valley Fever. The researchers found that blocking PD-1 essentially reinvigorated the T cells, producing interferon gamma that signals the immune system to fight the fungal infection better.
The other paper focuses on a second pattern of immune dysregulation that contributes to severe, disseminated Valley Fever. Here the researchers show how about 25% of patients have an immune system that is abnormally skewed toward a "Type 2" response, an immune program where Valley Fever is misinterpreted by the body as if it were an allergy or parasite rather than a fungus. Curiously, this Type 2 response was seen almost exclusively in males. In collaboration with Dr. Valerie Arboleda, associate professor of pathology at UCLA, the team delved into the genetic links to why some people develop this Type 2 response. They identified a set of rare genetic variants that explain the skewed responses in some, but most individuals remained genetically unsolved. Finally, they found that the allergy drug Dupilumab, which blocks overactive allergic immunity, reversed the skewing in the lab.
Moving beyond the bench to the clinic, the team has begun to employ these discoveries on the sickest Valley Fever patients referred to UCLA. In a paper published in March, the team described how they treated 18 severe cases with Interferon gamma to boost the immune system. They also treated 14 severe cases found to have Type 2 skewing with dupilumab, which retuned their 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 Butte, who is also chief of the pediatrics department's division of immunology, allergy, and rheumatology.
For instance, one person who was wheelchair bound is walking again. Another who had been on antifungals for several years and would be easily 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, Butte said. He also wants to expand the search for genetic underpinnings of dissemination and to explain why males are more likely to get sick.
Valley Fever, technically known as Coccidioidomycosis, is a dust-borne fungal infection that occurs in dry regions like the southwestern US and is proliferating in California and Arizona. California alone spends $1 billion a year on treatment.
Valley Fever starts in the lungs, but in rare occasions can spread to other parts of the body, even to the brain. It can be life-threatening, and even when it clears can leave the patient debilitated for years afterward. To combat this infection, physicians have long relied on antifungal drugs. But they don't always work when the infection has spread too extensively. To better understand why the infection spreads in some individuals, UCLA researchers found that patients with severe illness had an abnormal immune response. In some cases, the immune system was overactive; in other cases it was underactive. These findings opened new doors to treatment by modulating the immune system.
"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 to treating these infections: we give medicines to modulate the immune system to fight the infections better."
Dr. Butte has joint appointments in the Depts. of Microbiology, Immunology, and Molecular Genetics and Human Genetics.
Now, in two studies published in the peer-reviewed JCI Insight, the team delves into why some peoples' immune systems are unable to effectively combat the infection.
In one , the researchers examined the role of T cell exhaustion, which is when 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 pattern seen in exhausted T cells. T cell exhaustion is commonly seen when T cells fight cancers, and many oncologists nowadays employ treatments to undo the exhausted state and fight cancers better. Inspired by the successes of oncologists, Dr. Butte's team tried the same idea in Valley Fever. The researchers found that blocking PD-1 essentially reinvigorated the T cells, producing interferon gamma that signals the immune system to fight the fungal infection better.
The other paper focuses on a second pattern of immune dysregulation that contributes to severe, disseminated Valley Fever. Here the researchers show how about 25% of patients have an immune system that is abnormally skewed toward a "Type 2" response, an immune program where Valley Fever is misinterpreted by the body as if it were an allergy or parasite rather than a fungus. Curiously, this Type 2 response was seen almost exclusively in males. In collaboration with Dr. Valerie Arboleda, associate professor of pathology at UCLA, the team delved into the genetic links to why some people develop this Type 2 response. They identified a set of rare genetic variants that explain the skewed responses in some, but most individuals remained genetically unsolved. Finally, they found that the allergy drug Dupilumab, which blocks overactive allergic immunity, reversed the skewing in the lab.
Moving beyond the bench to the clinic, the team has begun to employ these discoveries on the sickest Valley Fever patients referred to UCLA. In a paper published in March, the team described how they treated 18 severe cases with Interferon gamma to boost the immune system. They also treated 14 severe cases found to have Type 2 skewing with dupilumab, which retuned their 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 Butte, who is also chief of the pediatrics department's division of immunology, allergy, and rheumatology.
For instance, one person who was wheelchair bound is walking again. Another who had been on antifungals for several years and would be easily 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, Butte said. He also wants to expand the search for genetic underpinnings of dissemination and to explain why males are more likely to get sick.
