title: CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival.
abstract: 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.
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Muthulekha
authors.initials: M
authors.lastname: Swamydas
authors.affiliation: Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Gao
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Break
authors.affiliation: Duke University School of Medicine, Durham, NC 27708, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen 6500HB, Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Jaeger
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, NY 10029, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rodriguez
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, NY 10029, USA.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Lim
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Nathaniel M
authors.initials: NM
authors.lastname: Green
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Collar
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA. Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Brett G
authors.initials: BG
authors.lastname: Fischer
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Chyi-Chia Richard
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Duke University School of Medicine, Durham, NC 27708, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.affiliation: Duke University School of Medicine, Durham, NC 27708, USA.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Alexander
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen 6500HB, Netherlands.
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen 6500HB, Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA. lionakism@niaid.nih.gov.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
mesh_terms: D000483:Alleles; D000818:Animals; D002175:Candida / Q000254:growth & development / Q000502:physiology*; D002177:Candidiasis / Q000097:blood / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D015550:Cell Degranulation; D054365:Chemokine CXCL5 / Q000378:metabolism; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D006801:Humans; D025301:Hyphae / Q000502:physiology; D007668:Kidney / Q000382:microbiology / Q000473:pathology; D008024:Ligands; D051379:Mice; D050296:Microbial Viability; D050505:Mutant Proteins / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D014019:Tissue Donors
chemical_list: D054365:Chemokine CXCL5; D008024:Ligands; D050505:Mutant Proteins; D023062:Receptors, Interleukin-8A