The Granuloma Response Controlling Cryptococcosis in Mice Depends on the Sphingosine Kinase 1-Sphingosine 1-Phosphate Pathway

Infect Immun. 2015 Jul;83(7):2705-13. doi: 10.1128/IAI.00056-15. Epub 2015 Apr 20.

Abstract

Cryptococcus neoformans is a fungal pathogen that causes pulmonary infections, which may progress into life-threatening meningitis. In commonly used mouse models of C. neoformans infections, fungal cells are not contained in the lungs, resulting in dissemination to the brain. We have previously reported the generation of an engineered C. neoformans strain (C. neoformans Δgcs1) which can be contained in lung granulomas in the mouse model and have shown that granuloma formation is dependent upon the enzyme sphingosine kinase 1 (SK1) and its product, sphingosine 1-phosphate (S1P). In this study, we have used four mouse models, CBA/J and C57BL6/J (both immunocompetent), Tgε26 (an isogenic strain of strain CBA/J lacking T and NK cells), and SK(-/-) (an isogenic strain of strain C57BL6/J lacking SK1), to investigate how the granulomatous response and SK1-S1P pathway are interrelated during C. neoformans infections. S1P and monocyte chemotactic protein-1 (MCP-1) levels were significantly elevated in the bronchoalveolar lavage fluid of all mice infected with C. neoformans Δgcs1 but not in mice infected with the C. neoformans wild type. SK1(-/-) mice did not show elevated levels of S1P or MCP-1. Primary neutrophils isolated from SK1(-/-) mice showed impaired antifungal activity that could be restored by the addition of extracellular S1P. In addition, high levels of tumor necrosis factor alpha were found in the mice infected with C. neoformans Δgcs1 in comparison to the levels found in mice infected with the C. neoformans wild type, and their levels were also dependent on the SK1-S1P pathway. Taken together, these results suggest that the SK1-S1P pathway promotes host defense against C. neoformans infections by regulating cytokine levels, promoting extracellular killing by phagocytes, and generating a granulomatous response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cryptococcosis / immunology
  • Cryptococcosis / pathology*
  • Cryptococcus neoformans / genetics
  • Cryptococcus neoformans / immunology
  • Cryptococcus neoformans / physiology*
  • Disease Models, Animal
  • Female
  • Gene Deletion
  • Granuloma / immunology
  • Granuloma / pathology*
  • Lung / microbiology
  • Lung / pathology
  • Lysophospholipids / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism

Substances

  • Lysophospholipids
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine