Abstract
Opportunistic fungi are a major cause of morbidity and mortality world-wide, particularly in immunocompromised individuals. Developing new treatments to combat invasive fungal disease is challenging given that fungal and mammalian host cells are eukaryotic, with similar organization and physiology. Even therapies targeting unique fungal cell features have limitations and drug resistance is emerging. New approaches to the development of antifungal drugs are therefore needed urgently. Cryptococcus neoformans, the commonest cause of fungal meningitis worldwide, is an accepted model for studying fungal pathogenicity and driving drug discovery. We recently characterized a phospholipase C (Plc1)-dependent pathway in C. neoformans comprising of sequentially-acting inositol polyphosphate kinases (IPK), which are involved in synthesizing inositol polyphosphates (IP). We also showed that the pathway is essential for fungal cellular function and pathogenicity. The IP products of the pathway are structurally diverse, each consisting of an inositol ring, with phosphate (P) and pyrophosphate (PP) groups covalently attached at different positions. This review focuses on (1) the characterization of the Plc1/IPK pathway in C. neoformans; (2) the identification of PP-IP5 (IP7) as the most crucial IP species for fungal fitness and virulence in a mouse model of fungal infection; and (3) why IPK enzymes represent suitable candidates for drug development.
Highlights
Opportunistic fungi are a major cause of morbidity and mortality world-wide, in immunocompromised individuals
In a mouse inhalation model, we found that infection with the cryptococcal PLC1 deletion mutant was cleared from the lung 14 days post-infection, and that the mutant failed to disseminate to the brain [75]
We observed that plc1∆ and the cryptococcal calcineurin deletion mutant shared significant phenotypic similarity under a range of stress conditions, suggesting that phospholipase C1 (Plc1)-derived IP3 could activate calcineurin in C. neoformans
Summary
Invasive fungal infections (IFIs) are a major cause of global morbidity and mortality. The majority of IFIs worldwide are caused by Aspergillus spp., Candida spp., Cryptococcus spp., and Pneumocystis jirovecii. Much of the burden of IFIs is on developing countries, which have high incidences of HIV/AIDS. According to a recent UNAIDS Global AIDS Report, 25.8 million people are estimated to be living. In addition to HIV/AIDs patients, IFIs pose a significant threat to solid organ and hematopoietic stem cell or bone marrow transplant recipients. IFIs are an enormous economic liability to the global health system: a US study found that transplant patients with an IFI stayed in hospital an additional 19 days longer than patients without an IFI, resulting in an excess of. There is a 5-fold increase in the mortality rate of these patients [9]
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