A defect in ATP-citrate lyase links acetyl-CoA production, virulence factor elaboration and virulence inCryptococcus neoformans

摘要: Summary The interaction of Cryptococcus neoformans with phagocytic cells the innate immune system is a key step in disseminated disease leading to meningoencephalitis immunocompromised individuals. Transcriptional profiling cryptococcal harvested from cell culture medium or macrophages found differential expression metabolic and other functions during fungal adaptation intracellular environment. We focused on ACL1 gene for ATP-citrate lyase, which converts citrate acetyl-CoA, because this showed elevated transcript levels importance acetyl-CoA as central metabolite. Mutants lacking delayed growth containing glucose, reduced cellular defective production virulence factors, increased susceptibility antifungal drug fluconazole decreased survival within macrophages. Importantly, acl1 mutants were unable cause murine inhalation model, phenotype that was more extreme than defects (e.g. an synthetase mutant). Loss likely due perturbation critical physiological interconnections between factor metabolism C. neoformans. Phylogenetic analysis structural modelling Acl1 identified three indels unique protein sequences; these differences may provide opportunities development pathogen-specific inhibitors.