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A defect in ATP ‐citrate lyase links acetyl‐ CoA production, virulence factor elaboration and virulence in C ryptococcus neoformans
The interaction of C ryptococcus neoformans with phagocytic cells of the innate immune system is a key step in disseminated disease leading to meningoencephalitis in immunocompromised individuals. Transcriptional profiling of cryptococcal cells harvested from cell culture medium or from macrophages...
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Published in: | Molecular microbiology 2012-12, Vol.86 (6), p.1404-1423 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The interaction of
C
ryptococcus neoformans
with phagocytic cells of the innate immune system is a key step in disseminated disease leading to meningoencephalitis in immunocompromised individuals. Transcriptional profiling of cryptococcal cells harvested from cell culture medium or from macrophages found differential expression of metabolic and other functions during fungal adaptation to the intracellular environment. We focused on the
ACL1
gene for
ATP
‐citrate lyase, which converts citrate to acetyl‐
CoA
, because this gene showed elevated transcript levels in macrophages and because of the importance of acetyl‐
CoA
as a central metabolite. Mutants lacking
ACL1
showed delayed growth on medium containing glucose, reduced cellular levels of acetyl‐
CoA
, defective production of virulence factors, increased susceptibility to the antifungal drug fluconazole and decreased survival within macrophages. Importantly,
acl1
mutants were unable to cause disease in a murine inhalation model, a phenotype that was more extreme than other mutants with defects in acetyl‐
CoA
production (e.g. an acetyl‐
CoA
synthetase mutant). Loss of virulence is likely due to perturbation of critical physiological interconnections between virulence factor expression and metabolism in
C
. neoformans
. Phylogenetic analysis and structural modelling of cryptococcal
Acl1
identified three indels unique to fungal protein sequences; these differences may provide opportunities for the development of pathogen‐specific inhibitors. |
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ISSN: | 0950-382X 1365-2958 |
DOI: | 10.1111/mmi.12065 |