Success of Candida as a pathogen may depend partly on high frequency switching between general phenotypes and their associated expression of hypothetical sets of virulence genes that in the composite (but not singularly) facilitate and constitute a strain's pathogenic behavior. One putative virulence factor, Candida acid proteinase (CAP), is differentially expressed by switch phenotypes, facilitates pathogenic behavior, and is a prime candidate for membership in the hypothetical set of Candida virulence genes. We ask: 1) Do specific switch phenotypes and their CAP secretion correlate with commensal or pathogenic behavior? 2) Do patient titers of CAP antibody or antigen correlate with infection, phenotypes and CAP secretion? 3) Do switch phenotypes and CAP secretion relate to observed and experimental pathogenic behavior? The project will determine if switch phenotypes and CAP discriminate between commensal and pathogenic Candida isolates, and correlate with human and experimental animal infections. 1. Quantitation of CAP Secretion by Commensal and Pathogenic Candida Isolates and Phenotypes. Commensal and pathogenic isolates and their phenotypes from normals and patients with candidiasis, will be obtained. CAP secretion of each phenotype will be assessed and correlated with 1) commensal or pathogenic behavior of isolates and switch phenotypes in patients and 2) the pathogenicity of phenotypes in experimental candidiasis. 2. CAP Antibody Response and Antigenic Presence in Mucocutaneous and Systemic Candidiasis. Sera of patients at risk to or with systemic candidiasis, or with mucocutaneous candidiasis and those with Candida colonization, will be obtained. CAP antibody and antigen will be measured by ELISA and latex agglutination. Tissue of infections will be tested for CAP deposits by immunofluorescent methods. CAP antigen in sera and tissue and CAP antibody titers will be correlated with clinical manifestations, the patient's isolate and switch phenotypes and their CAP secretion. Predictive values of CAP antibody and antigen titers in sera for infections will be determined. The secretion and presence of CAP in vivo with be correlated with infecting strains and switch phenotypes. 3. Pathogenicity of Candida Isolates and Their Switch Phenotypes in Experimental Candidiasis. Virulence of commensal and pathogenic isolates and switch phenotypes from Candida infections will be tested in murine models of candidiasis. Virulence will be correlated with isolate behavior in the patient of, origin, the switch phenotype used, and CAP secretion. This will demonstrate the role of switch phenotypes and CAP secretion in experimental infections to compare with clinical infections. Transitions from commensal to pathogenic phenotypes through switching and CAP secretion may be elucidated.
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