Urea Amidolyase (DUR1,2) Contributes to Virulence and Kidney Pathogenesis of Candida albicans

Dhammika H.M.L.P. Navarathna, Michail S. Lionakis, Martin J. Lizak, Jeeva Munasinghe, Kenneth W. Nickerson, David D. Roberts

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The intracellular enzyme urea amidolyase (Dur1,2p) enables C. albicans to utilize urea as a sole nitrogen source. Because deletion of the DUR1,2 gene reduces survival of C. albicans co-cultured with a murine macrophage cell line, we investigated the role of Dur1,2p in pathogenesis using a mouse model of disseminated candidiasis. A dur1,2Δ/dur1,2Δ strain was significantly less virulent than the wild-type strain, showing significantly higher survival rate, better renal function, and decreased and less sustained fungal colonization in kidney and brain. Complementation of the mutant restored virulence. DUR1,2 deletion resulted in a milder host inflammatory reaction. Immunohistochemistry, flow cytometry, and magnetic resonance imaging showed decreased phagocytic infiltration into infected kidneys. Systemic cytokine levels of wild-type mice infected with the dur1,2 mutant showed a more balanced systemic pro-inflammatory cytokine response. Host gene expression and protein analysis in infected kidneys revealed parallel changes in the local immune response. Significant differences were observed in the kidney IL-1 inflammatory pathway, IL-15 signaling, MAP kinase signaling, and the alternative complement pathway. We conclude that Dur1,2p is important for kidney colonization during disseminated candidiasis and contributes to an unbalanced host inflammatory response and subsequent renal failure. Therefore, this Candida-specific enzyme may represent a useful drug target to protect the host from kidney damage associated with disseminated candidiasis.

Original languageEnglish (US)
Article numbere48475
JournalPloS one
Volume7
Issue number10
DOIs
StatePublished - Oct 29 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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