title: CX3CR1-dependent renal macrophage survival promotes Candida control and host survival.
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.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
authors.forename: Muthulekha
authors.initials: M
authors.lastname: Swamydas
authors.forename: Brett G
authors.initials: BG
authors.lastname: Fischer
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Martin
authors.initials: M
authors.lastname: Jaeger
authors.forename: Nathaniel M
authors.initials: NM
authors.lastname: Green
authors.forename: Andrius
authors.initials: A
authors.lastname: Masedunskas
authors.forename: Roberto
authors.initials: R
authors.lastname: Weigert
authors.forename: Constantinos
authors.initials: C
authors.lastname: Mikelis
authors.forename: Wuzhou
authors.initials: W
authors.lastname: Wan
authors.forename: Chyi-Chia Richard
authors.initials: CC
authors.lastname: Lee
authors.forename: Jean K
authors.initials: JK
authors.lastname: Lim
authors.forename: Aymeric
authors.initials: A
authors.lastname: Rivollier
authors.forename: John C
authors.initials: JC
authors.lastname: Yang
authors.forename: Greg M
authors.initials: GM
authors.lastname: Laird
authors.forename: Robert T
authors.initials: RT
authors.lastname: Wheeler
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Alexander
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Gao
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D000073883:CX3C Chemokine Receptor 1; D002176:Candida albicans / Q000276:immunology / Q000502:physiology* / Q000648:ultrastructure; D058365:Candidiasis, Invasive / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000502:physiology; D054428:Chemokine CX3CL1 / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D025301:Hyphae / Q000648:ultrastructure; D007668:Kidney / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000382:microbiology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009000:Monocytes / Q000382:microbiology / Q000502:physiology; D009426:Netherlands; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D011828:Radiation Chimera; D054390:Receptors, CCR2 / Q000502:physiology; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012307:Risk Factors; D013047:Specific Pathogen-Free Organisms; D014481:United States
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C515963:Traf3ip2 protein, mouse