Abstract
Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a mouse model of systemic candidiasis, we found that resident macrophages accumulated in the kidney, the main target organ of infection, and formed direct contacts with the fungus in vivo mainly within the first few hours after infection. Macrophage accumulation and contact with Candida were both markedly reduced in mice lacking chemokine receptor CX3CR1, which was found almost exclusively on resident macrophages in uninfected kidneys. Infected Cx3cr1-/- mice uniformly succumbed to Candida-induced renal failure, but exhibited clearance of the fungus in all other organs tested. Renal macrophage deficiency in infected Cx3cr1-/- mice was due to reduced macrophage survival, not impaired proliferation, trafficking, or differentiation. In humans, the dysfunctional CX3CR1 allele CX3CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX3CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis.
Publication types
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Comparative Study
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Multicenter Study
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology
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Adoptive Transfer
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Animals
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Apoptosis
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CX3C Chemokine Receptor 1
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Candida albicans / immunology
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Candida albicans / physiology*
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Candida albicans / ultrastructure
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Candidiasis, Invasive / immunology*
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Candidiasis, Invasive / pathology
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Cell Movement
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Chemokine CCL2 / physiology
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Chemokine CX3CL1 / physiology
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Female
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Genetic Predisposition to Disease
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Host-Pathogen Interactions / immunology
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Humans
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Hyphae / ultrastructure
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Kidney / immunology*
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Kidney / microbiology
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Kidney / pathology
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Macrophage Activation
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Macrophages / microbiology
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Macrophages / physiology*
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Male
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Mice
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Mice, Inbred C57BL
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Models, Animal
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Monocytes / microbiology
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Monocytes / physiology
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Netherlands
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Organ Specificity
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Polymorphism, Single Nucleotide
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Radiation Chimera
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Receptors, CCR2 / physiology
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Receptors, Chemokine / deficiency
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Receptors, Chemokine / genetics
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Receptors, Chemokine / physiology*
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Risk Factors
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Specific Pathogen-Free Organisms
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United States
Substances
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Adaptor Proteins, Signal Transducing
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CX3C Chemokine Receptor 1
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CX3CR1 protein, human
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Ccl2 protein, mouse
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Ccr2 protein, mouse
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Chemokine CCL2
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Chemokine CX3CL1
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Cx3cl1 protein, mouse
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Cx3cr1 protein, mouse
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Receptors, CCR2
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Receptors, Chemokine
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Traf3ip2 protein, mouse