ABSTRACT
Carbon dioxide (CO(2)) and its hydration product bicarbonate (HCO(3)(-)) are essential molecules in various physiological processes of all living organisms. The reversible interconversion between CO(2) and HCO(3)(-) is in equilibrium. This reaction is slow without catalyst, but can be rapidly facilitated by Zn(2+)-metalloenzymes named carbonic anhydrases (CAs). To gain an insight into the function of multiple clades of fungal CA, we chose to investigate the filamentous fungi Aspergillus fumigatus and A. nidulans. We identified four and two CAs in A. fumigatus and A. nidulans, respectively, named cafA-D and canA-B. The cafA and cafB genes are constitutively, strongly expressed whereas cafC and cafD genes are weakly expressed but CO(2)-inducible. Heterologous expression of the A. fumigatus cafB, and A. nidulans canA and canB genes completely rescued the high CO(2)-requiring phenotype of a Saccharomyces cerevisiae Deltance103 mutant. Only the DeltacafA DeltacafB and DeltacanB deletion mutants were unable to grow at 0.033% CO(2), of which growth defects can be restored by high CO(2). Defects in the CAs can affect Aspergilli conidiation. Furthermore, A. fumigatus DeltacafA, DeltacafB, DeltacafC, DeltacafD and DeltacafA DeltacafB mutant strains are fully virulent in a low-dose murine infection.
Subject(s)
Aspergillus fumigatus/enzymology , Aspergillus nidulans/enzymology , Carbonic Anhydrases/metabolism , Fungal Proteins/metabolism , Amino Acid Sequence , Animals , Aspergillosis/microbiology , Aspergillosis/pathology , Aspergillus fumigatus/genetics , Aspergillus fumigatus/growth & development , Aspergillus nidulans/genetics , Carbon Dioxide/metabolism , Carbonic Anhydrases/genetics , Cluster Analysis , DNA, Fungal/genetics , Disease Models, Animal , Fungal Proteins/genetics , Gene Deletion , Gene Expression Profiling , Genetic Complementation Test , Mice , Molecular Sequence Data , Phylogeny , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae/metabolism , Sequence Alignment , Sequence Homology , Spores, Fungal/growth & development , Survival Analysis , VirulenceABSTRACT
Aspergillus fumigatus is a ubiquitous saprophytic fungus responsible for organic material decomposition, and plays an important role in recycling environmental carbon and nitrogen. Besides its important role in the environment, this fungus has been reported as one of the most important fungal pathogens in immunocompromised patients. Due to changes in CO2 concentration that some pathogens face during the infection process, studies have been undertaken to understand the pathogenic roles of carbonic anhydrases (CAs), well-known CO2 hydration catalytic enzymes. As a basis for a discussion of the possible roles of CAs in A. fumigatus pathogenicity, this review describes the main characteristics of the A. fumigatus infection and the challenges for its treatment. In addition, it gathers findings from studies with CA inhibitor drugs as anti-infective agents in different pathogens.