title: Human Immune Response Varies by the Degree of Relative Cryptococcal Antigen Shedding.
abstract: Background.  Cerebrospinal fluid (CSF) cryptococcal glucuronoxylomannan antigen (CrAg) titers generally correlate with quantitative fungal culture burden; however, correlation is not precise. Some patients have higher CrAg titers with lower fungal burdens and vice versa. We hypothesized that the relative discordancy between CrAg titer and quantitative culture burden reflects the relative degree of CrAg shedding by Cryptococcus neoformans and is associated with human immune responses. Methods.  One hundred ninety human immunodeficiency virus-infected individuals with cryptococcal meningitis were enrolled in Uganda and South Africa. We compared initial CSF CrAg titers relative to their CSF quantitative cultures to determine low (n = 58), intermediate (n = 68), or high (n = 64) CrAg shedders. We compared cytokines measured by Luminex multiplex assay on cryopreserved CSF and 10-week mortality across shedding groups using linear and logistic regression and distribution of genotypes by multilocus sequence typing. Results.  The relative degree of CrAg shedding was positively associated with increasing CSF levels of the following: interleukin (IL)-6, IL-7, IL-8, and tumor necrosis factor-α (each P < 0.01), which are all secreted by antigen-presenting cells and negatively associated with vascular endothelial growth factor (P = .01). In addition, IL-5, IL-13, granulocyte colony-stimulating factor, and macrophage chemotactic protein were decreased in low-CrAg shedders compared with intermediate shedders (each P ≤ .01). Type 1 T-helper cells (Th1) cytokine responses and 10-week mortality did not differ between the shedding groups. Cryptococcal genotypes were equally distributed across shedding groups. Conclusions.  Discordancy between CrAg shedding and expected shedding based on quantitative fungal burden is associated with detectable immunologic differences in CSF, primarily among secreted cytokines and chemokines produced by antigen-presenting cells and Th2.
authors.affiliation: Division of Infectious Diseases and International Medicine, Department of Medicine; School of Public Health.
authors.forename: David R
authors.initials: DR
authors.lastname: Boulware
authors.affiliation: Division of Infectious Diseases and International Medicine, Department of Medicine.
authors.forename: Maximilian
authors.initials: M
authors.lastname: von Hohenberg
authors.affiliation: Division of Infectious Diseases and International Medicine, Department of Medicine; School of Public Health.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Rolfes
authors.affiliation: Division of Infectious Diseases and International Medicine, Department of Medicine.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Bahr
authors.affiliation: Division of Infectious Diseases and International Medicine, Department of Medicine; Infectious Disease Institute, Makerere University.
authors.forename: Joshua
authors.initials: J
authors.lastname: Rhein
authors.affiliation: Makerere University College of Health Sciences , Kampala.
authors.forename: Andrew
authors.initials: A
authors.lastname: Akampurira
authors.affiliation: Division of Infectious Diseases and International Medicine, Department of Medicine; Infectious Disease Institute, Makerere University.
authors.forename: Darlisha A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Mbarara University of Science and Technology , Uganda.
authors.forename: Kabanda
authors.initials: K
authors.lastname: Taseera
authors.affiliation: Infectious Diseases Unit, GF Jooste Hospital; Department of Medicine, Faculty of Health Sciences; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schutz
authors.affiliation: Department of Microbiology and Immunology , University of Minnesota , Minnesota.
authors.forename: Tami
authors.initials: T
authors.lastname: McDonald
authors.affiliation: Mbarara University of Science and Technology , Uganda.
authors.forename: Conrad
authors.initials: C
authors.lastname: Muzoora
authors.affiliation: Infectious Diseases Unit, GF Jooste Hospital; Department of Medicine, Faculty of Health Sciences; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Division of Infectious Diseases and International Medicine, Department of Medicine; Infectious Disease Institute, Makerere University; Makerere University College of Health Sciences, Kampala.
authors.forename: David B
authors.initials: DB
authors.lastname: Meya
authors.affiliation: Department of Microbiology and Immunology , University of Minnesota , Minnesota.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nielsen
authors.affiliation: School of Public Health.
authors.forename: Katherine
authors.initials: K
authors.lastname: Huppler Hullsiek
keywords: Cryptococcus; HIV/AIDS; cerebrospinal fluid; cryptococcal meningitis; immune response