Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice
ABSTRACT We assessed the role of Dectin-1 in the immune response to the pathogenic fungus Coccidioides, both in vitro and in vivo, using mice with a targeted mutation in Clec7a. Elicited peritoneal macrophages responded to formalin-killed spherules (FKS) and alkali-treated FKS by secreting proinflam...
Guardado en:
Autores principales: | , , , , |
---|---|
Formato: | article |
Lenguaje: | EN |
Publicado: |
American Society for Microbiology
2013
|
Materias: | |
Acceso en línea: | https://doaj.org/article/0d26f57a83574493a5ee87b848c2e7d4 |
Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
id |
oai:doaj.org-article:0d26f57a83574493a5ee87b848c2e7d4 |
---|---|
record_format |
dspace |
spelling |
oai:doaj.org-article:0d26f57a83574493a5ee87b848c2e7d42021-11-15T15:40:22ZDectin-1 Is Required for Resistance to Coccidioidomycosis in Mice10.1128/mBio.00597-122150-7511https://doaj.org/article/0d26f57a83574493a5ee87b848c2e7d42013-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00597-12https://doaj.org/toc/2150-7511ABSTRACT We assessed the role of Dectin-1 in the immune response to the pathogenic fungus Coccidioides, both in vitro and in vivo, using mice with a targeted mutation in Clec7a. Elicited peritoneal macrophages responded to formalin-killed spherules (FKS) and alkali-treated FKS by secreting proinflammatory cytokines in a Dectin-1- and β-glucan-dependent manner. The responses of bone marrow-derived dendritic cells (BMDC) to the same stimulants were more complex; interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) secretion was independent of Dectin-1, while IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were largely but not entirely dependent on Dectin-1. After intranasal infection, Dectin-1−/− mice had lower concentrations of IL-12p70, gamma interferon (IFN-γ), IL-1β, and the Th17 cytokines IL-22, IL-23, and 17A in the lung lavage fluid, which may explain why they were significantly more susceptible to pulmonary coccidioidomycosis two weeks after infection. The Dectin-1 mutation was even more deleterious in (B6 × DBA/2)F2 mice, which are more resistant to coccidioidomycosis than B6 mice by virtue of protective genes from DBA/2, a genetically resistant strain. We also found that two susceptible strains of mice (B6 and BALB/c) expressed much less Dectin-1 in their lungs than did resistant DBA/2 mice. We conclude that Dectin-1 is necessary for resistance to Coccidioides immitis, that Dectin-1 promotes both Th1 and Th17 protective immune responses to this infection, and that there is a correlation between expression of Dectin-1 by the inflammatory infiltrate and resistance to coccidioidomycosis. IMPORTANCE Coccidioidomycosis is a fungal infection endemic in the southwestern United States and neighboring Mexico, causing ~150,000 lung infections in people and resulting in ~17,000 hospitalizations annually in California alone. Very little is known about innate immunity to this fungus. This paper shows that Dectin-1, the primary β-glucan receptor on myeloid cells, is required for resistance to this pathogen. Dectin-1 is part of the innate immune system, and it is needed to direct the acquired immune response toward into a pathway that will lead to macrophage activation. Lungs from infected mice lacking Dectin-1 had lower concentrations of Th1 and Th17 cytokines, two cytokine pathways that are very important for acquired T cell immunity to Coccidioides spp. This is the first demonstration that Dectin-1 is required for host resistance to a dimorphic, primary pathogenic fungus.Suganya ViriyakosolMaria del Pilar JimenezMichael A. GurneyMark E. AshbaughJoshua FiererAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 1 (2013) |
institution |
DOAJ |
collection |
DOAJ |
language |
EN |
topic |
Microbiology QR1-502 |
spellingShingle |
Microbiology QR1-502 Suganya Viriyakosol Maria del Pilar Jimenez Michael A. Gurney Mark E. Ashbaugh Joshua Fierer Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice |
description |
ABSTRACT We assessed the role of Dectin-1 in the immune response to the pathogenic fungus Coccidioides, both in vitro and in vivo, using mice with a targeted mutation in Clec7a. Elicited peritoneal macrophages responded to formalin-killed spherules (FKS) and alkali-treated FKS by secreting proinflammatory cytokines in a Dectin-1- and β-glucan-dependent manner. The responses of bone marrow-derived dendritic cells (BMDC) to the same stimulants were more complex; interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) secretion was independent of Dectin-1, while IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were largely but not entirely dependent on Dectin-1. After intranasal infection, Dectin-1−/− mice had lower concentrations of IL-12p70, gamma interferon (IFN-γ), IL-1β, and the Th17 cytokines IL-22, IL-23, and 17A in the lung lavage fluid, which may explain why they were significantly more susceptible to pulmonary coccidioidomycosis two weeks after infection. The Dectin-1 mutation was even more deleterious in (B6 × DBA/2)F2 mice, which are more resistant to coccidioidomycosis than B6 mice by virtue of protective genes from DBA/2, a genetically resistant strain. We also found that two susceptible strains of mice (B6 and BALB/c) expressed much less Dectin-1 in their lungs than did resistant DBA/2 mice. We conclude that Dectin-1 is necessary for resistance to Coccidioides immitis, that Dectin-1 promotes both Th1 and Th17 protective immune responses to this infection, and that there is a correlation between expression of Dectin-1 by the inflammatory infiltrate and resistance to coccidioidomycosis. IMPORTANCE Coccidioidomycosis is a fungal infection endemic in the southwestern United States and neighboring Mexico, causing ~150,000 lung infections in people and resulting in ~17,000 hospitalizations annually in California alone. Very little is known about innate immunity to this fungus. This paper shows that Dectin-1, the primary β-glucan receptor on myeloid cells, is required for resistance to this pathogen. Dectin-1 is part of the innate immune system, and it is needed to direct the acquired immune response toward into a pathway that will lead to macrophage activation. Lungs from infected mice lacking Dectin-1 had lower concentrations of Th1 and Th17 cytokines, two cytokine pathways that are very important for acquired T cell immunity to Coccidioides spp. This is the first demonstration that Dectin-1 is required for host resistance to a dimorphic, primary pathogenic fungus. |
format |
article |
author |
Suganya Viriyakosol Maria del Pilar Jimenez Michael A. Gurney Mark E. Ashbaugh Joshua Fierer |
author_facet |
Suganya Viriyakosol Maria del Pilar Jimenez Michael A. Gurney Mark E. Ashbaugh Joshua Fierer |
author_sort |
Suganya Viriyakosol |
title |
Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice |
title_short |
Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice |
title_full |
Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice |
title_fullStr |
Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice |
title_full_unstemmed |
Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice |
title_sort |
dectin-1 is required for resistance to coccidioidomycosis in mice |
publisher |
American Society for Microbiology |
publishDate |
2013 |
url |
https://doaj.org/article/0d26f57a83574493a5ee87b848c2e7d4 |
work_keys_str_mv |
AT suganyaviriyakosol dectin1isrequiredforresistancetococcidioidomycosisinmice AT mariadelpilarjimenez dectin1isrequiredforresistancetococcidioidomycosisinmice AT michaelagurney dectin1isrequiredforresistancetococcidioidomycosisinmice AT markeashbaugh dectin1isrequiredforresistancetococcidioidomycosisinmice AT joshuafierer dectin1isrequiredforresistancetococcidioidomycosisinmice |
_version_ |
1718427746984525824 |