Abstract
The Nlrp3 inflammasome has been proposed to play an important role in antifungal host defense. However, studies exploring the role of the inflammasome in antifungal host defense have been limited to the direct effects on IL-1β processing. Although IL-1β has important direct effects on the innate immune response, important effects of the caspase-1-dependent cytokines IL-1β and IL-18 are exerted on the initiation of the adaptive Th1 and Th17 cellular responses. No studies have been employed to assess the impact of the inflammasome on the Th1/Th17 defense mechanisms in vivo during candidiasis. In the present study, we demonstrate an essential role for caspase-1 and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) in disseminated candidiasis through regulating antifungal Th1 and Th17 responses. Caspase-1(-/-) and ASC(-/-) mice display diminished Th1/Th17 responses, followed by increased fungal outgrowth and lower survival. These observations identify a critical role for the inflammasome in controlling protective adaptive immune responses during invasive fungal infection.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins
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Bone Marrow Cells / immunology
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Bone Marrow Cells / metabolism
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CARD Signaling Adaptor Proteins
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Candida albicans / immunology
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Candida albicans / physiology
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Candidiasis / immunology*
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Candidiasis / microbiology
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Caspase 1 / genetics
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Caspase 1 / immunology
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Caspase 1 / metabolism
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / immunology
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Cytoskeletal Proteins / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Enzyme-Linked Immunosorbent Assay
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Female
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Flow Cytometry
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Genetic Predisposition to Disease
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Host-Pathogen Interactions / immunology
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Immunity, Cellular / immunology
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Inflammasomes / genetics
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Inflammasomes / immunology*
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Inflammasomes / metabolism
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Interleukin-18 / genetics
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Interleukin-18 / immunology
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Interleukin-18 / metabolism
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Kidney / immunology
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Kidney / microbiology
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Kidney / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Th1 Cells / immunology*
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Th1 Cells / metabolism
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Th17 Cells / immunology*
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Th17 Cells / metabolism
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Cytoskeletal Proteins
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Inflammasomes
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Interleukin-18
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Interleukin-1beta
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Pycard protein, mouse
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Tumor Necrosis Factor-alpha
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Caspase 1