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Defects in phosphate acquisition and storage influence virulence of Cryptococcus neoformans.
- Source :
-
Infection and immunity [Infect Immun] 2014 Jul; Vol. 82 (7), pp. 2697-712. Date of Electronic Publication: 2014 Apr 07. - Publication Year :
- 2014
-
Abstract
- Nutrient acquisition and sensing are critical aspects of microbial pathogenesis. Previous transcriptional profiling indicated that the fungal pathogen Cryptococcus neoformans, which causes meningoencephalitis in immunocompromised individuals, encounters phosphate limitation during proliferation in phagocytic cells. We therefore tested the hypothesis that phosphate acquisition and polyphosphate metabolism are important for cryptococcal virulence. Deletion of the high-affinity uptake system interfered with growth on low-phosphate medium, perturbed the formation of virulence factors (capsule and melanin), reduced survival in macrophages, and attenuated virulence in a mouse model of cryptococcosis. Additionally, analysis of nutrient sensing functions for C. neoformans revealed regulatory connections between phosphate acquisition and storage and the iron regulator Cir1, cyclic AMP (cAMP)-dependent protein kinase A (PKA), and the calcium-calmodulin-activated protein phosphatase calcineurin. Deletion of the VTC4 gene encoding a polyphosphate polymerase blocked the ability of C. neoformans to produce polyphosphate. The vtc4 mutant behaved like the wild-type strain in interactions with macrophages and in the mouse infection model. However, the fungal load in the lungs was significantly increased in mice infected with vtc4 deletion mutants. In addition, the mutant was impaired in the ability to trigger blood coagulation in vitro, a trait associated with polyphosphate. Overall, this study reveals that phosphate uptake in C. neoformans is critical for virulence and that its regulation is integrated with key signaling pathways for nutrient sensing.<br /> (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Animals
Biological Transport drug effects
Biological Transport genetics
Biological Transport physiology
Cell Line
Cyclosporine pharmacology
Fungal Proteins genetics
Fungal Proteins metabolism
Gene Expression Regulation, Fungal
Mice
Mice, Inbred BALB C
Mutation
Polyphosphates metabolism
Virulence
Zinc pharmacology
Cryptococcosis microbiology
Cryptococcus neoformans pathogenicity
Cryptococcus neoformans physiology
Phosphates metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5522
- Volume :
- 82
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Infection and immunity
- Publication Type :
- Academic Journal
- Accession number :
- 24711572
- Full Text :
- https://doi.org/10.1128/IAI.01607-14