Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis.
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 mecha...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-05-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1004884 |
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| author | Anil A Panackal Simone C Wuest Yen-Chih Lin Tianxia Wu Nannan Zhang Peter Kosa Mika Komori Andrew Blake Sarah K Browne Lindsey B Rosen Ferry Hagen Jacques Meis Stuart M Levitz Martha Quezado Dima Hammoud John E Bennett Bibi Bielekova Peter R Williamson |
| author_facet | Anil A Panackal Simone C Wuest Yen-Chih Lin Tianxia Wu Nannan Zhang Peter Kosa Mika Komori Andrew Blake Sarah K Browne Lindsey B Rosen Ferry Hagen Jacques Meis Stuart M Levitz Martha Quezado Dima Hammoud John E Bennett Bibi Bielekova Peter R Williamson |
| author_sort | Anil A Panackal |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6500928e698640418cf123c97e812eac |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2015-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-6500928e698640418cf123c97e812eac2025-08-20T02:22:38ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-05-01115e100488410.1371/journal.ppat.1004884Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis.Anil A PanackalSimone C WuestYen-Chih LinTianxia WuNannan ZhangPeter KosaMika KomoriAndrew BlakeSarah K BrowneLindsey B RosenFerry HagenJacques MeisStuart M LevitzMartha QuezadoDima HammoudJohn E BennettBibi BielekovaPeter R WilliamsonThe 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.https://doi.org/10.1371/journal.ppat.1004884 |
| spellingShingle | Anil A Panackal Simone C Wuest Yen-Chih Lin Tianxia Wu Nannan Zhang Peter Kosa Mika Komori Andrew Blake Sarah K Browne Lindsey B Rosen Ferry Hagen Jacques Meis Stuart M Levitz Martha Quezado Dima Hammoud John E Bennett Bibi Bielekova Peter R Williamson Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. PLoS Pathogens |
| title | Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. |
| title_full | Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. |
| title_fullStr | Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. |
| title_full_unstemmed | Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. |
| title_short | Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. |
| title_sort | paradoxical immune responses in non hiv cryptococcal meningitis |
| url | https://doi.org/10.1371/journal.ppat.1004884 |
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