Biomedical subjects

John M Shea

Publications and source records attributed to John M Shea.

3 recordsLinked to original sources

PubMed2006

Lipid signaling in pathogenic fungi.

Recent studies have highlighted the importance of lipid signaling molecules in the development and pathogenicity of clinically important fungi. In Cryptococcus neoformans, sphingolipid-derived diacylglycerol has been shown to induce the transcription of the putative virulence factor App1, which inhibits the phagocytosis of fungal cells by alveolar macrophages, as well as to activate the protein kinase C Pkc1, which promotes cell-wall stability and increased melanin production. In Candida albicans, exposure to the oxylipin farnesol causes the regulation of specific genes involved in hyphal development, drug resistance and iron acquisition. Farnesol increases resistance to oxidative stress in C. albicans but, interestingly, induces apoptotic-like cell death in Aspergillus nidulans, suggesting that this molecule has multiple and opposing functions. Finally, fungal cells secrete eicosanoids, which are lipid molecules with putative signaling functions in fungi, and the recent characterization of the first fungal enzymes associated with the production of eicosanoids in A. nidulans and Aspergillus fumigatus provides new insights into the understanding of the role of eicosanoid production in the biology of fungal pathogenesis.

Animals↗

PubMed2006

Lipid metabolism in Cryptococcus neoformans.

In recent years, lipids have been shown to act as signalling molecules not only in mammalian cells but also in many other eukaryotes. Whereas in mammalian cells lipids regulate cellular functions that play crucial roles in the regulation of pathobiological processes, such as cancer, cardiovascular and neurodegenerative disorders, and inflammation, in the fungus Cryptococcus neoformans lipids play key roles in the regulation of pathogenic traits required for the development of cryptococcosis, an infectious disease particularly frequent in immunocompromised individuals. In this minireview we discuss recent advances in the understanding of lipid metabolism in this important human pathogen, highlighting the potential of fungal lipid enzymatic pathways as promising new drug targets.

Animals↗

PubMed2006

The cryptococcal enzyme inositol phosphosphingolipid-phospholipase C confers resistance to the antifungal effects of macrophages and promotes fungal dissemination to the central nervous system.

In recent years, sphingolipids have emerged as critical molecules in the regulation of microbial pathogenesis. In fungi, the synthesis of complex sphingolipids is important for the regulation of pathogenicity, but the role of sphingolipid degradation in fungal virulence is not known. Here, we isolated and characterized the inositol phosphosphingolipid-phospholipase C1 (ISC1) gene from the fungal pathogen Cryptococcus neoformans and showed that it encodes an enzyme that metabolizes fungal inositol sphingolipids. Isc1 protects C. neoformans from acidic, oxidative, and nitrosative stresses, which are encountered by the fungus in the phagolysosomes of activated macrophages, through a Pma1-dependent mechanism(s). In an immunocompetent mouse model, the C. neoformans Deltaisc1 mutant strain is almost exclusively found extracellularly and in a hyperencapsulated form, and its dissemination to the brain is remarkably reduced compared to that of control strains. Interestingly, the dissemination of the C. neoformans Deltaisc1 strain to the brain is promptly restored in these mice when alveolar macrophages are pharmacologically depleted or when infecting an immunodeficient mouse in which macrophages are not efficiently activated. These studies suggest that Isc1 plays a key role in protecting C. neoformans from the intracellular environment of macrophages, whose activation is important for preventing fungal dissemination of the Deltaisc1 strain to the central nervous system and the development of meningoencephalitis.

Amino Acid Sequence↗