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Open AccessArticle

Monocyte Phenotype and IFN-γ-Inducible Cytokine Responses Are Associated with Cryptococcal Immune Reconstitution Inflammatory Syndrome

Infectious Diseases Institute, Makerere University, Kampala, P.O. Box 22418, Uganda
Dept of Medicine, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, MN 55455, USA
School of Medicine, College of Health Sciences, Makerere University, Kampala, P.O. Box 7072, Uganda
Research Department, Makerere University Walter Reed Project, Plot 42, Nakasero Road, Kampala, P.O. Box 1624, Uganda
London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK
MRC/UVRI Uganda Research Unit on AIDS, UVRI, Entebbe, Plot 51-59 Nakiwogo Road, Uganda
School of Biomedical Sciences, Microbiology Department, Makerere University, Kampala P.O. Box 7072, Uganda
Division of Infectious Diseases, Department of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA
National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA
Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver, Aurora, CO 80045, USA
Author to whom correspondence should be addressed.
Academic Editor: Adilia Warris
J. Fungi 2017, 3(2), 28;
Received: 1 April 2017 / Revised: 11 May 2017 / Accepted: 27 May 2017 / Published: 2 June 2017
(This article belongs to the Special Issue Host–Fungus Interactions)
A third of adults with AIDS and cryptococcal meningitis (CM) develop immune reconstitution inflammatory syndrome (IRIS) after initiating antiretroviral therapy (ART), which is thought to result from exaggerated inflammatory antigen-specific T cell responses. The contribution of monocytes to the immunopathogenesis of cryptococcal IRIS remains unclear. We compared monocyte subset frequencies and immune responses in HIV-infected Ugandans at time of CM diagnosis (IRIS-Baseline) for those who later developed CM-IRIS, controls who did not develop CM-IRIS (Control-Baseline) at CM-IRIS (IRIS-Event), and for controls at a time point matched for ART duration (Control-Event) to understand the association of monocyte distribution and immune responses with cryptococcal IRIS. At baseline, stimulation with IFN-γ ex vivo induced a higher frequency of TNF-α- and IL-6-producing monocytes among those who later developed IRIS. Among participants who developed IRIS, ex vivo IFN-γ stimulation induced higher frequencies of activated monocytes, IL-6+, TNF-α+ classical, and IL-6+ intermediate monocytes compared with controls. In conclusion, we have demonstrated that monocyte subset phenotype and cytokine responses prior to ART are associated with and may be predictive of CM-IRIS. Larger studies to further delineate innate immunological responses and the efficacy of immunomodulatory therapies during cryptococcal IRIS are warranted. View Full-Text
Keywords: cryptococcal meningitis; Cryptococcus; HIV; monocytes; innate immune response; IRIS cryptococcal meningitis; Cryptococcus; HIV; monocytes; innate immune response; IRIS
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Meya, D.B.; Okurut, S.; Zziwa, G.; Cose, S.; Bohjanen, P.R.; Mayanja-Kizza, H.; Joloba, M.; Boulware, D.R.; Yukari Manabe, C.; Wahl, S.; Janoff, E.N. Monocyte Phenotype and IFN-γ-Inducible Cytokine Responses Are Associated with Cryptococcal Immune Reconstitution Inflammatory Syndrome. J. Fungi 2017, 3, 28.

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