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

Publication ,  Journal Article
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 ...
Published in: Sci Transl Med
January 20, 2016

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.

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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

January 20, 2016

Volume

8

Issue

322

Start / End Page

322ra10

Location

United States

Related Subject Headings

  • Tissue Donors
  • Survival Analysis
  • Receptors, Interleukin-8A
  • Polymorphism, Single Nucleotide
  • Neutrophils
  • Mutant Proteins
  • Microbial Viability
  • Mice
  • Ligands
  • Kidney
 

Citation

APA
Chicago
ICMJE
MLA
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Swamydas, M., Gao, J.-L., Break, T. J., Johnson, M. D., Jaeger, M., Rodriguez, C. A., … Lionakis, M. S. (2016). CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival. Sci Transl Med, 8(322), 322ra10. https://doi.org/10.1126/scitranslmed.aac7718
Swamydas, Muthulekha, Ji-Liang Gao, Timothy J. Break, Melissa D. Johnson, Martin Jaeger, Carlos A. Rodriguez, Jean K. Lim, et al. “CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival.Sci Transl Med 8, no. 322 (January 20, 2016): 322ra10. https://doi.org/10.1126/scitranslmed.aac7718.
Swamydas M, Gao J-L, Break TJ, Johnson MD, Jaeger M, Rodriguez CA, et al. CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival. Sci Transl Med. 2016 Jan 20;8(322):322ra10.
Swamydas, Muthulekha, et al. “CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival.Sci Transl Med, vol. 8, no. 322, Jan. 2016, p. 322ra10. Pubmed, doi:10.1126/scitranslmed.aac7718.
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. CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival. Sci Transl Med. 2016 Jan 20;8(322):322ra10.

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

January 20, 2016

Volume

8

Issue

322

Start / End Page

322ra10

Location

United States

Related Subject Headings

  • Tissue Donors
  • Survival Analysis
  • Receptors, Interleukin-8A
  • Polymorphism, Single Nucleotide
  • Neutrophils
  • Mutant Proteins
  • Microbial Viability
  • Mice
  • Ligands
  • Kidney