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Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans
Philipp C. Rittershaus, … , Chiara Luberto, Maurizio Del Poeta
Philipp C. Rittershaus, … , Chiara Luberto, Maurizio Del Poeta
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1651-1659. https://doi.org/10.1172/JCI27890.
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Research Article Microbiology

Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans

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Abstract

The pathogenic fungus Cryptococcus neoformans infects humans upon inhalation and causes the most common fungal meningoencephalitis in immunocompromised subjects worldwide. In the host, C. neoformans is found both intracellularly and extracellularly, but how these two components contribute to the development of the disease is largely unknown. Here we show that the glycosphingolipid glucosylceramide (GlcCer), which is present in C. neoformans, was essential for fungal growth in host extracellular environments, such as in alveolar spaces and in the bloodstream, which are characterized by a neutral/alkaline pH, but not in the host intracellular environment, such as in the phagolysosome of macrophages, which is characteristically acidic. Indeed, a C. neoformans mutant strain lacking GlcCer did not grow in vitro at a neutral/alkaline pH, yet it had no growth defect at an acidic pH. The mechanism by which GlcCer regulates alkali tolerance was by allowing the transition of C. neoformans through the cell cycle. This study establishes C. neoformans GlcCer as a key virulence factor of cryptococcal pathogenicity, with important implications for future development of new antifungal strategies.

Authors

Philipp C. Rittershaus, Talar B. Kechichian, Jeremy C. Allegood, Alfred H. Merrill, Mirko Hennig, Chiara Luberto, Maurizio Del Poeta

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Figure 1

Expression of GCS1 genes in S. cerevisiae.

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Expression of GCS1 genes in S. cerevisiae.
(A) In vivo labeling in S. ce...
(A) In vivo labeling in S. cerevisiae with [3H]-DHS. Expression of cryptococcal and human GCS1 produced GlcCer (boxed region) in galactose (+), but not in glucose (–). DHS, dihydrosphingosine; S1P, sphingosine-1-phosphate. Inositol phosphoryl ceramide (IPC), mannose-IPC (MIPC), and mannose-(inositol phosphoryl)2 ceramide (MIP2C) are complex sphingolipids. (B) In vitro assay in S. cerevisiae using NBD-C6-ceramides. Proteins extracted from yeast cells expressing pYES2-HuGCS1 and incubated with NBD-ceramides produced NBD-GlcCer under induction by galactose. NBD-GlcCer production was not observed in yeast cells expressing pYES2-CnGCS1 or pYES2 empty vector.
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