Affiliation:
1. Department of Biochemistry and Molecular Biology
2. Department of Microbiology and Immunology
3. Department of Craniofacial Biology
4. Division of Infectious Diseases, Medical University of South Carolina, Charleston, South Carolina
Abstract
ABSTRACT
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 (Δ
gcs1
), 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
Δ
gcs1
, 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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Immunology,Microbiology,Parasitology
Cited by
30 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献