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Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis
Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529209/ https://www.ncbi.nlm.nih.gov/pubmed/26252005 http://dx.doi.org/10.1371/journal.ppat.1005040 |
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author | Sionov, Edward Mayer-Barber, Katrin D. Chang, Yun C. Kauffman, Keith D. Eckhaus, Michael A. Salazar, Andres M. Barber, Daniel L. Kwon-Chung, Kyung J. |
author_facet | Sionov, Edward Mayer-Barber, Katrin D. Chang, Yun C. Kauffman, Keith D. Eckhaus, Michael A. Salazar, Andres M. Barber, Daniel L. Kwon-Chung, Kyung J. |
author_sort | Sionov, Edward |
collection | PubMed |
description | Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6C(high) monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in RORγt+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFNγ KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses. |
format | Online Article Text |
id | pubmed-4529209 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-45292092015-08-12 Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis Sionov, Edward Mayer-Barber, Katrin D. Chang, Yun C. Kauffman, Keith D. Eckhaus, Michael A. Salazar, Andres M. Barber, Daniel L. Kwon-Chung, Kyung J. PLoS Pathog Research Article Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6C(high) monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in RORγt+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFNγ KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses. Public Library of Science 2015-08-07 /pmc/articles/PMC4529209/ /pubmed/26252005 http://dx.doi.org/10.1371/journal.ppat.1005040 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Sionov, Edward Mayer-Barber, Katrin D. Chang, Yun C. Kauffman, Keith D. Eckhaus, Michael A. Salazar, Andres M. Barber, Daniel L. Kwon-Chung, Kyung J. Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis |
title | Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis |
title_full | Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis |
title_fullStr | Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis |
title_full_unstemmed | Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis |
title_short | Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis |
title_sort | type i ifn induction via poly-iclc protects mice against cryptococcosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529209/ https://www.ncbi.nlm.nih.gov/pubmed/26252005 http://dx.doi.org/10.1371/journal.ppat.1005040 |
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