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.

Sphingolipids as Targets for Treatment of Fungal Infections

“…A variety of studies have recently shown that affecting enzymes involved in these sphingolipid biosynthetic pathways using inhibitors or gene deletion can attenuate the virulence of fungal pathogens such as, Candida albicans, Cryptococcus neoformans and Aspergillus spp. [13][14][15]. Several natural inhibitors of fungal GlcCer synthesis have been described to exhibit a potent antifungal activity [16][17][18].…”

Sphingolipids from the human fungal pathogen Aspergillus fumigatus

“…Biological functions of GlcCer in fungi have been studied through gene deletion and inhibitory approaches. The interruption of any steps of the GlcCer biosynthetic pathway leads to a defect in growth, morphology and virulence in yeast and filamentous fungal pathogen [23][24][25]. Among Aspergillus species, GlcCer biosynthesis and functions have been mainly investigated in A. nidulans, a model filamentous fungus.…”

“…Plant and mammalian fungal pathogens, deficient in GlcCer, are less virulent [24,27,29,78,79]. The role of GlcCer, required for the full virulence of human fungal pathogen C. neoformans has been more investigated [25]. GlcCer deficient yeast does not present growth defect in acidic pH but do not growth at a neutral/alkaline pH which is essential for the fungal growth in host extracellular environment [25].…”

“…The role of GlcCer, required for the full virulence of human fungal pathogen C. neoformans has been more investigated [25]. GlcCer deficient yeast does not present growth defect in acidic pH but do not growth at a neutral/alkaline pH which is essential for the fungal growth in host extracellular environment [25]. In contrast, the deletion of ISC1, coding for an inositol phosphosphingolipid-phospholipase C, enhances the sensitivity of yeast to oxidative stresses and to acidic environments.…”

Role of sphingosine-1-phosphate (S1P) and S1P receptor 2 in the phagocytosis of Cryptococcus neoformans by alveolar macrophages

“…However, C. neoformans is a facultative intracellular pathogen capable of surviving not only in the extracellular environment of the alveolar spaces but also intracellularly within AMs (Feldmesser et al, 2000). Thus, when AMs are unable to kill intracellular C. neoformans, internalization of C. neoformans is detrimental to the host as it provides a protective environment that promotes survival and can exacerbate the dissemination from the lung to other organs (Chrétien et al, 2002;Goldman et al, 2000;Kechichian et al, 2007;Levitz et al, 1999;Luberto et al, 2003;Rittershaus et al, 2006). Therefore, it is important to our understanding of the pathogenesis of C. neoformans to define the host factors modulating the effector functions of AMs, specifically phagocytosis, in order to develop new anticryptococcal therapeutic regiments.…”