Dataset Information

The involvement of the Mid1/Cch1/Yvc1 calcium channels in Aspergillus fumigatus virulence.

ABSTRACT: Aspergillus fumigatus is a major opportunistic pathogen and allergen of mammals. Calcium homeostasis and signaling is essential for numerous biological processes and also influences A. fumigatus pathogenicity. The presented study characterized the function of the A. fumigatus homologues of three Saccharomyces cerevisiae calcium channels, voltage-gated Cch1, stretch-activated Mid1 and vacuolar Yvc1. The A. fumigatus calcium channels cchA, midA and yvcA were regulated at transcriptional level by increased calcium levels. The YvcA::GFP fusion protein localized to the vacuoles. Both ?cchA and ?midA mutant strains showed reduced radial growth rate in nutrient-poor minimal media. Interestingly, this growth defect in the ?cchA strain was rescued by the exogenous addition of CaCl2. The ?cchA, ?midA, and ?cchA ?midA strains were also sensitive to the oxidative stress inducer, paraquat. Restriction of external Ca(2+) through the addition of the Ca(2+)-chelator EGTA impacted upon the growth of the ?cchA and ?midA strains. All the A. fumigatus ?cchA, ?midA, and ?yvcA strains demonstrated attenuated virulence in a neutropenic murine model of invasive pulmonary aspergillosis. Infection with the parental strain resulted in a 100% mortality rate at 15 days post-infection, while the mortality rate of the ?cchA, ?midA, and ?yvcA strains after 15 days post-infection was only 25%. Collectively, this investigation strongly indicates that CchA, MidA, and YvcA play a role in A. fumigatus calcium homeostasis and virulence.

SUBMITTER: de Castro PA

PROVIDER: S-EPMC4118995 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

The involvement of the Mid1/Cch1/Yvc1 calcium channels in Aspergillus fumigatus virulence.

de Castro Patrícia Alves PA Chiaratto Jéssica J Winkelströter Lizziane K LK Bom Vinícius Leite Pedro VL Ramalho Leandra Naira Zambelli LN Goldman Maria Helena S MH Brown Neil Andrew NA Goldman Gustavo H GH

PloS one 20140801 8

Aspergillus fumigatus is a major opportunistic pathogen and allergen of mammals. Calcium homeostasis and signaling is essential for numerous biological processes and also influences A. fumigatus pathogenicity. The presented study characterized the function of the A. fumigatus homologues of three Saccharomyces cerevisiae calcium channels, voltage-gated Cch1, stretch-activated Mid1 and vacuolar Yvc1. The A. fumigatus calcium channels cchA, midA and yvcA were regulated at transcriptional level by i ...[more]

PMID: 25083783

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Project description:Aspergillus fumigatus is a major opportunistic fungal pathogen of immunocompromised and immunocompetent hosts. To successfully establish an infection, A. fumigatus needs to use host carbon sources, such as acetate, present in the body fluids and peripheral tissues. However, utilization of acetate as a carbon source by fungi in the context of infection has not been investigated. This work shows that acetate is metabolized via different pathways in A. fumigatus and that acetate utilization is under the regulatory control of a transcription factor (TF), FacB. A. fumigatus acetate utilization is subject to carbon catabolite repression (CCR), although this is only partially dependent on the TF and main regulator of CCR CreA. The available extracellular carbon source, in this case glucose and acetate, significantly affected A. fumigatus virulence traits such as secondary metabolite secretion and cell wall composition, with the latter having consequences for resistance to oxidative stress, antifungal drugs, and human neutrophil-mediated killing. Furthermore, deletion of facB significantly impaired the in vivo virulence of A. fumigatus in both insect and mammalian models of invasive aspergillosis. This is the first report on acetate utilization in A. fumigatus, and this work further highlights the importance of available host-specific carbon sources in shaping fungal virulence traits and subsequent disease outcome, and a potential target for the development of antifungal strategies. IMPORTANCE Aspergillus fumigatus is an opportunistic fungal pathogen in humans. During infection, A. fumigatus is predicted to use host carbon sources, such as acetate, present in body fluids and peripheral tissues, to sustain growth and promote colonization and invasion. This work shows that A. fumigatus metabolizes acetate via different pathways, a process that is dependent on the transcription factor FacB. Furthermore, the type and concentration of the extracellular available carbon source were determined to shape A. fumigatus virulence determinants such as secondary metabolite secretion and cell wall composition. Subsequently, interactions with immune cells are altered in a carbon source-specific manner. FacB is required for A. fumigatus in vivo virulence in both insect and mammalian models of invasive aspergillosis. This is the first report that characterizes acetate utilization in A. fumigatus and highlights the importance of available host-specific carbon sources in shaping virulence traits and potentially subsequent disease outcome.

Dataset Information

The involvement of the Mid1/Cch1/Yvc1 calcium channels in Aspergillus fumigatus virulence.

Publications

The involvement of the Mid1/Cch1/Yvc1 calcium channels in Aspergillus fumigatus virulence.

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