Human immune response varies by the degree of relative cryptococcal antigen shedding

David R. Boulware, Maximilian von Hohenberg, Melissa A. Rolfes, Nathan C. Bahr, Joshua Rhein, Andrew Akampurira, Darlisha A. Williams, Kabanda Taseera, Charlotte Schutz, Tami McDonald, Conrad Muzoora, Graeme Meintjes, David B. Meya, Kirsten Nielsen, Katherine Huppler Hullsiek, Abdu K. Musubire, Henry W. Nabeta, Friedrich Thienemann, Radha Rajasingham, James E. ScrivenJames Mwesigy, Robert Wagubi, Henry Kajumbula, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Liberica Ndyatunga, Busingye Noeme, Brian Memela, Yolisa Sigila, Alisat Sadiq, Monica Magwayi, Richard Kwizera, Emily Ninsiima, Grace Najjuka, Anna Strain, Darin Wiesner, Catherine Nanteza, Rhina Mushagara, Leya Hassanally, Mariam Namawejje, Mark Ssennono, Agnes Kiragga, Elissa K. Butler, For the Cryptococcal Optimal ART Timing (COAT) Trial Team

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14 Scopus citations


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.

Original languageEnglish (US)
JournalOpen Forum Infectious Diseases
Issue number1
StatePublished - Jan 1 2016

Bibliographical note

Publisher Copyright:
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.


  • Cerebrospinal fluid
  • Cryptococcal meningitis
  • Cryptococcus
  • Immune response


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