Abstract
The elements of the cellular immune response in human coccidioidomycosis remain undefined. We examined the ex vivo release of an array of inflammatory proteins in response to incubation with a coccidioidal antigen preparation to ascertain which of these might be associated with diagnosis and outcome. Patients with a recent diagnosis of primary pulmonary coccidioidomycosis and a control group of healthy subjects were studied. Blood samples were incubated for 18h with T27K, a soluble coccidioidal preparation containing multiple glycosylated antigens, and the supernatant was assayed for inflammatory proteins using the multiplex Luminex system. The presentation and course of illness were compared to the levels of the inflammatory proteins. Among the 31 subjects studied, the median time from diagnosis to assay was 15days. Of the 30 inflammatory proteins measured, the levels of only 7 proteins, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor alpha (IL-1RA), interleukin-1β (IL-1β), interferon gamma (IFN-γ), IL-2, IL-13, and tumor necrosis factor alpha (TNF-α), were more than 10-fold above the levels seen without antigen stimulation. The levels of IFN-γ and IL-2 were significantly elevated in those subjects not receiving triazole antifungal therapy compared to those who were receiving triazole antifungal therapy. While the levels of IL-1RA were nonspecifically elevated, elevated levels of IL-13 were seen only in those with active pulmonary coccidioidomycosis. Only six cytokines were specifically increased in subjects with recently diagnosed primary pulmonary coccidioidomycosis. While IFN-γ, IL-2, and TNF-α have been previously noted, the finding of elevated levels of the innate cytokines GM-CSF and IL-1β could suggest that these, as well as IL-13, are early and specific markers for pulmonary coccidioidomycosis.IMPORTANCE Coccidioidomycosis, commonly known as Valley fever, is a common pneumonia in the southwestern United States. In this paper, we examined the release of 30 inflammatory proteins in whole-blood samples obtained from persons with coccidioidal pneumonia after the blood samples were incubated with a preparation made from the causative fungus, Coccidioides We found that six of these proteins, all cytokines, were specifically released in high concentrations in these patients. Three of the cytokines were seen very early in disease, and an assay for all six might serve as a marker for the early diagnosis of Valley fever.
Highlights
The elements of the cellular immune response in human coccidioidomycosis remain undefined
We have previously shown that the coccidioidal antigen preparation T27K induces a specific ex vivo cellular immune response among humans with coccidioidomycosis that correlates with delayed type hypersensitivity to coccidioidin skin testing [6]
While we have previously shown that the T-helper type 1 cytokines IL-2, IFN-␥, and TNF-␣ are released ex vivo when exposed to coccidioidal antigen [5, 7, 8], the findings for the other cytokines are new and unexpected
Summary
The elements of the cellular immune response in human coccidioidomycosis remain undefined. We examined the ex vivo release of an array of inflammatory proteins in response to incubation with a coccidioidal antigen preparation to ascertain which of these might be associated with diagnosis and outcome. We have previously shown that the coccidioidal antigen preparation T27K induces a specific ex vivo cellular immune response among humans with coccidioidomycosis that correlates with delayed type hypersensitivity to coccidioidin skin testing [6] These studies have focused principally on the T-helper type 1 cytokines interferon gamma (IFN-␥), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-␣). We have broadened our approach and attempted to determine what other cytokines, chemokines, and growth factors are released ex vivo in response to incubation of whole-blood samples with T27K, studying subjects with recently diagnosed primary pulmonary coccidioidomycosis. (This work was presented in part at the 7th International Coccidioidomycosis Symposium held 10 to 13 August 2017 at Stanford University.)
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