CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival.

Journal Article

Systemic Candida albicans infection causes high morbidity and mortality and is now the leading cause of nosocomial bloodstream infection in the United States. Neutropenia is a major risk factor for poor outcome in infected patients; however, the molecular factors that mediate neutrophil trafficking and effector function during infection are poorly defined. Using a mouse model of systemic candidiasis, we found that the neutrophil-selective CXC chemokine receptor Cxcr1 and its ligand, Cxcl5, are highly induced in the Candida-infected kidney, the target organ in the model. To investigate the role of Cxcr1 in antifungal host defense in vivo, we generated Cxcr1(-/-) mice and analyzed their immune response to Candida. Mice lacking Cxcr1 exhibited decreased survival with enhanced Candida growth in the kidney and renal failure. Increased susceptibility of Cxcr1(-/-) mice to systemic candidiasis was not due to impaired neutrophil trafficking from the blood into the infected kidney but was the result of defective killing of the fungus by neutrophils that exhibited a cell-intrinsic decrease in degranulation. In humans, the mutant CXCR1 allele CXCR1-T276 results in impaired neutrophil degranulation and fungal killing and was associated with increased risk of disseminated candidiasis in infected patients. Together, our data demonstrate a biological function for mouse Cxcr1 in vivo and indicate that CXCR1-dependent neutrophil effector function is a critical innate protective mechanism of fungal clearance and host survival in systemic candidiasis.

Full Text

Duke Authors

Cited Authors

  • Swamydas, M; Gao, J-L; Break, TJ; Johnson, MD; Jaeger, M; Rodriguez, CA; Lim, JK; Green, NM; Collar, AL; Fischer, BG; Lee, C-CR; Perfect, JR; Alexander, BD; Kullberg, B-J; Netea, MG; Murphy, PM; Lionakis, MS

Published Date

  • January 2016

Published In

Volume / Issue

  • 8 / 322

Start / End Page

  • 322ra10 -

PubMed ID

  • 26791948

Electronic International Standard Serial Number (EISSN)

  • 1946-6242

International Standard Serial Number (ISSN)

  • 1946-6234

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.aac7718

Language

  • eng