Initial interactions


One of the leading causes of hospital-acquired infection in immune compromised patients is the fungus, Candida albicans.  Among patients, both the risk of developing candidiasis and the clinical outcome is variable, indicating that host-dependent factors contribute to C. albicans infection and disease progression. Using a murine candidiasis model, Michail Lionakis and colleagues at the National Institute of Allergy and Infectious Diseases determined that C. albicans interacts with macrophages in the kidney during the initial stages of infection and this interaction is mediated by the chemokine receptor CX3CR1. Mice lacking this receptor succumbed to C. albicans-induced kidney failure; however, these mice had exhibited fungal clearance in other organs prior to death. Furthermore, human patients with a mutation in the gene encoding CX3CR1 were at higher risk of candidiasis. This study identifies an important role for CX3CR1-meditated interaction of C. albicans and macrophages in controlling disease progression and outcome. The micrographs above are representative sections from PAS-stained murine kidney. In the kidney of WT mice (left), C. albicans (magenta) is contained within distinct foci: however, in the kidney of Cx3cr1-/- mice (right), C. albicans is seen throughout the tissue.

Published November 1, 2013, by Corinne Williams

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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 December 2, 2013; First published November 1, 2013
Citation Information: J Clin Invest. 2013;123(12):5035-5051. https://doi.org/10.1172/JCI71307.
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Categories: 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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