Abstract
In vitro studies have indicated the importance of Toll-like receptor (TLR) signaling in response to the fungal pathogens Candida albicans and Aspergillus fumigatus. However, the functional consequences of the complex interplay between fungal morphogenesis and TLR signaling in vivo remain largely undefined. In this study we evaluate the impact of the IL-1R/TLR/myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway on the innate and adaptive Th immunities to C. albicans and A. fumigatus in vivo. It was found that 1) the MyD88-dependent pathway is required for resistance to both fungi; 2) the involvement of the MyD88 adapter may occur through signaling by distinct members of the IL-1R/TLR superfamily, including IL-1R, TLR2, TLR4, and TLR9, with the proportional role of the individual receptors varying depending on fungal species, fungal morphotypes, and route of infection; 3) individual TLRs and IL-1R activate specialized antifungal effector functions on neutrophils, which correlates with susceptibility to infection; and 4) MyD88-dependent signaling on dendritic cells is crucial for priming antifungal Th1 responses. Thus, the finding that the innate and adaptive immunities to C. albicans and A. fumigatus require the coordinated action of distinct members of the IL-1R/TLR superfamily acting through MyD88 makes TLR manipulation amenable to the induction of host resistance to fungi.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antifungal Agents / metabolism
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Antigens, Differentiation / genetics
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Antigens, Differentiation / physiology
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Aspergillosis / genetics
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Aspergillosis / immunology
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Aspergillus fumigatus / immunology*
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Candida albicans / immunology*
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Candidiasis / genetics
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Candidiasis / immunology
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Female
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Genetic Predisposition to Disease
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Immunity, Cellular / genetics
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Immunity, Innate / genetics
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88
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Neutrophils / immunology
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Neutrophils / metabolism
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Neutrophils / microbiology
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / physiology*
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Receptors, Immunologic / deficiency
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology
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Receptors, Interleukin-1 / deficiency
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / physiology*
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / metabolism
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Adaptor Proteins, Signal Transducing
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Antifungal Agents
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Antigens, Differentiation
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Interleukin-1
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha