Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans
Philipp C. Rittershaus, Talar B. Kechichian, Jeremy C. Allegood, Alfred H. Merrill, Mirko Hennig, Chiara Luberto, Maurizio Del Poeta
Philipp C. Rittershaus, Talar B. Kechichian, Jeremy C. Allegood, Alfred H. Merrill, Mirko Hennig, Chiara Luberto, Maurizio Del Poeta
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Research Article Microbiology

Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans

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 4

Histopathology of 2 different lungs obtained from CBA/J mice infected intranasally with the C. neoformans Δgsc1 strain.

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Histopathology of 2 different lungs obtained from CBA/J mice infected in...
(A and B) Movat stain. (C and D) Verhoeff–van Gieson stain. Boxed areas in A and C are magnified in B and D. In A, white arrowhead indicates C. neoformans cells stained alcian blue, white arrow indicates necrotic tissue, black arrowheads indicate macrophages, black arrows indicate lymphocyte infiltration with fibroblasts and fibrotic tissue, and green arrows indicate normal lung tissue. In B, yeast cells (white arrowhead) were found within necrotic tissue. Also, many yeast cells appear as “ghosts” or degenerated cells (yellow arrowheads) within macrophages. In C, black arrowhead indicates collagen stained red in the peripheral of a nodule containing necrotic tissue, yeast cells, macrophages, and lymphocytes. In D, note the collagen deposition (red stain) between lymphocytes and fibrotic tissue. A giant cell in gray (black arrowheads) was loaded with C. neoformans in the internal side of the nodule, surrounded by granulocytes and lymphocytes. Scale bars: 500 μm (A and C); 50 μm (B and D).