Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis

PLoS Pathogens

Bibi Bielekova¹  Jacques Meis²  Stuart M. Levitz²  Martha Quezado³  Dima Hammoud⁴  Simone C. Wuest⁵  Ferry Hagen⁶  Lindsey B. Rosen⁶  Peter Kosa⁶  Peter R. Williamson⁶  Anil A. Panackal⁶  John E. Bennett⁷  Yen-Chih Lin⁸  Sarah K. Browne⁸  Andrew Blake⁸  Mika Komori⁸  Nannan Zhang⁸  Tianxia Wu⁸ 

[1] Center for Infectious Disease Imaging, Radiology and Imaging Sciences, National Institutes of Health/Clinical Center, Bethesda, Maryland, United States of America;Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands;Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands;Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America;Division of Infectious Diseases, Department of Medicine, F. Hebert School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, United States of America;Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, United States of America;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America;Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America

关键词: T cells;    Cerebrospinal fluid;    Cryptococcus;    Immune response;    Macrophages;    Cytotoxic T cells;    Autopsy;    Cytokines;   

DOI  :  10.1371/journal.ppat.1004884

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.

【 授权许可】

CC BY