CX3CR1-dependent renal macrophage survival promotes Candida control and host survival
Michail S. Lionakis, … , Mihai G. Netea, Philip M. Murphy
Michail S. Lionakis, … , Mihai G. Netea, Philip M. Murphy
Published November 1, 2013
Citation Information: J Clin Invest. 2013;123(12):5035-5051. https://doi.org/10.1172/JCI71307.
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Research Article Infectious disease

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

Michail S. Lionakis, Muthulekha Swamydas, Brett G. Fischer, Theo S. Plantinga, Melissa D. Johnson, Martin Jaeger, Nathaniel M. Green, Andrius Masedunskas, Roberto Weigert, Constantinos Mikelis, Wuzhou Wan, Chyi-Chia Richard Lee, Jean K. Lim, Aymeric Rivollier, John C. Yang, Greg M. Laird, Robert T. Wheeler, Barbara D. Alexander, John R. Perfect, Ji-Liang Gao, Bart-Jan Kullberg, Mihai G. Netea, Philip M. Murphy

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Figure 2

Systemic candidiasis is uniformly fatal in Cx3cr1–/– mice due to uncontrolled fungal proliferation in the kidney and renal failure.

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Systemic candidiasis is uniformly fatal in Cx3cr1–/– mice due to uncontr...
(A) Mortality. Data represent summary results from Ccr2+/+ and Ccr2–/– mice (left; n = 15; 2 independent experiments), Cx3cr1+/+ and Cx3cr1–/– mice (middle; n = 33–35; 3 independent experiments), and Cx3cr1+/+, Cx3cr1gfp/+ and Cx3cr1gfp/gfp mice (right; n = 25–29; 2 independent experiments; P < 0.0001 for Cx3cr1+/+ versus Cx3cr1gfp/gfp, P < 0.0001 for Cx3cr1gfp/+ versus Cx3cr1gfp/gfp mice; P = 0.09 for Cx3cr1+/+ versus Cx3cr1gfp/+ mice). (B) Weight loss. *P < 0.01 (n = 23–24; 2 independent experiments). (C) Fungal burden in the kidney. *P = 0.02; **P < 0.001 (n = 19–23; 3 independent experiments). (D) PAS staining. Cross-sections of Cx3cr1+/+ and Cx3cr1–/– kidneys on day 6 after Candida infection (n = 8; 3 independent experiments). Original magnification, ×200. (E) Candida fungal balls in the Cx3cr1gfp/gfp renal pelvis. Confocal images of Cx3cr1gfp/+ and Cx3cr1gfp/gfp kidney at day 6 after infection with dTomato-expressing Candida (n = 3; 2 independent experiments). Scale bars: 200 μm. Objective, ×2. (F) Anatomic pathology of infected kidneys. Representative kidneys are shown for 2 mice of each genotype sacrificed at day 9 after infection. (G) Renal function. *P < 0.001 (n = 8–10; 2 independent experiments). (H) Histopathology. Representative H&E staining of kidney sections at day 9 after infection. Original magnification, ×20 (top row); ×100 (bottom row) (n = 8; 3 independent experiments). (I) Proinflammatory cytokine induction at day 9 after infection. *P = 0.03. **P < 0.01 (n = 8–10, day 9 after infection; 2 independent experiments). All quantitative data represent mean ± SEM.