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

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 repo...

Full description

Saved in:
Bibliographic Details
Published in:Infection and immunity 2015-07, Vol.83 (7), p.2705-2713
Main Authors: Farnoud, Amir M, Bryan, Arielle M, Kechichian, Talar, Luberto, Chiara, Del Poeta, Maurizio
Format: Article
Language:English
Subjects:
Animals
Bronchoalveolar Lavage Fluid - chemistry
Cryptococcosis - immunology
Cryptococcosis - pathology
Cryptococcus neoformans
Cryptococcus neoformans - genetics
Cryptococcus neoformans - immunology
Cryptococcus neoformans - physiology
Disease Models, Animal
Female
Fungal and Parasitic Infections
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.00056-15