Role of Host Sphingosine Kinase 1 in the Lung Response against Cryptococcosis

Cryptococcus neoformans is a fungal pathogen causing pulmonary infection and a life-threatening meningoencephalitis in human hosts. The fungus infects the host through inhalation, and thus, the host response in the lung environment is crucial for containment or dissemination of C. neoformans to othe...

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Bibliographic Details
Published in:Infection and Immunity 2010-05, Vol.78 (5), p.2342-2352
Main Authors: McQuiston, Travis, Luberto, Chiara, Del Poeta, Maurizio
Format: Article
Language:English
Subjects:
Alveoli
Animals
Biological and medical sciences
Brain
Collagen
Colony Count, Microbial
Cryptococcosis
Cryptococcosis - microbiology
Cryptococcosis - pathology
Cryptococcus neoformans
Cryptococcus neoformans - immunology
Female
Fundamental and applied biological sciences. Psychology
Fungal and Parasitic Infections
Glycosphingolipids
Granuloma
Granuloma - immunology
Granuloma - pathology
Immune response
Immunosuppression
Infection
Inhalation
Lung
Lung - microbiology
Lung - pathology
Macrophages
Macrophages, Alveolar - immunology
Macrophages, Alveolar - microbiology
Male
Meningoencephalitis
Mice
Mice, Inbred C57BL
Mice, Knockout
Microbiology
Pathogens
Phagocytosis
Phosphotransferases (Alcohol Group Acceptor) - deficiency
Phosphotransferases (Alcohol Group Acceptor) - physiology
Signal transduction
sphingosine kinase
Survival Analysis
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Summary:Cryptococcus neoformans is a fungal pathogen causing pulmonary infection and a life-threatening meningoencephalitis in human hosts. The fungus infects the host through inhalation, and thus, the host response in the lung environment is crucial for containment or dissemination of C. neoformans to other organs. In the lung, alveolar macrophages (AMs) are key players in the host lung immune response, and upon phagocytosis, they can kill C. neoformans by evoking an effective immune response through a variety of signaling molecules. On the other hand, under conditions not yet fully defined, the fungus is able to survive and proliferate within macrophages. Since the host sphingosine kinase 1 (SK1) regulates many signaling functions of immune cells, particularly in macrophages, in this study we determined the role of SK1 in the host response to C. neoformans infection. Using wild-type (SK1/2⁺/⁺) and SK1-deficient (SK1⁻/⁻) mice, we found that SK1 is dispensable during infection with a facultative intracellular wild-type C. neoformans strain. However, SK1 is required to form a host lung granuloma and to prevent brain infection by a C. neoformans mutant strain lacking the cell wall-associated glycosphingolipid glucosylceramide (Δgcs1), previously characterized as a mutant able to replicate only intracellularly. Specifically, in contrast to those from SK1/2⁺/⁺ mice, lungs from SK1⁻/⁻ mice have no collagen deposition upon infection with C. neoformans Δgcs1, and AMs from these mice contain significantly more C. neoformans cells than AMs from SK1/2⁺/⁺ mice, suggesting that under conditions in which C. neoformans is more internalized by AMs, SK1 may become important to control C. neoformans infection. Indeed, when we induced immunosuppression, a host condition in which wild-type C. neoformans cells are increasingly found intracellularly, SK1⁻/⁻ survived significantly less than SK1/2⁺/⁺ mice infected with a facultative intracellular wild-type strain, suggesting that SK1 has an important role in controlling C. neoformans infection under conditions in which the fungus is predominantly found intracellularly.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.01140-09