The Aspergillus fumigatus pkcA G579R mutant is defective in the activation of the cell wall integrity pathway but is dispensable for virulence in a neutropenic mouse infection model

A - Papers appearing in refereed journals

Rocha, M. C., De Godoy, K. F., De Castro, P. A., Hori, J. I., Bom, V. L. P., Brown, N. A., Da Cunha, A. F., Goldman, G. H. and Malavazi, I. 2015. The Aspergillus fumigatus pkcA G579R mutant is defective in the activation of the cell wall integrity pathway but is dispensable for virulence in a neutropenic mouse infection model. PLOS ONE. 10, p. e0135195.

AuthorsRocha, M. C., De Godoy, K. F., De Castro, P. A., Hori, J. I., Bom, V. L. P., Brown, N. A., Da Cunha, A. F., Goldman, G. H. and Malavazi, I.
Abstract

Aspergillus fumigatus is an opportunistic human pathogen, which causes the life-threatening disease, invasive pulmonary aspergillosis. In fungi, cell wall homeostasis is controlled by the conserved Cell Wall Integrity (CWI) pathway. In A. fumigatus this signaling cascade is partially characterized, but the mechanisms by which it is activated are not fully elucidated. In this study we investigated the role of protein kinase C (PkcA) in this signaling cascade. Our results suggest that pkcA is an essential gene and is activated in response to cell wall stress. Subsequently, we constructed and analyzed a non-essential A. fumigatus pkcAG579R mutant, carrying a Gly579Arg substitution in the PkcA C1B regulatory domain. The pkcAG579R mutation has a reduced activation of the downstream Mitogen-Activated Protein Kinase, MpkA, resulting in the altered expression of genes encoding cell wall-related proteins, markers of endoplasmic reticulum stress and the unfolded protein response. Furthermore, PkcAG579R is involved in the formation of proper conidial architecture and protection to oxidative damage. The pkcAG579R mutant elicits increased production of TNF-α and phagocytosis but it has no impact on virulence in a murine model of invasive pulmonary aspergillosis. These results highlight the importance of PkcA to the CWI pathway but also indicated that additional regulatory circuits may be involved in the biosynthesis and/or reinforcement of the A. fumigatus cell wall during infection.

Year of Publication2015
JournalPLOS ONE
Journal citation10, p. e0135195
Digital Object Identifier (DOI)doi:10.1371/journal.pone.0135195
Open accessPublished as ‘gold’ (paid) open access
FunderBiotechnology and Biological Sciences Research Council
Funder project or codePathogen-Host Interactions Database: PHI Database [2012-2017]
Publisher's version
Output statusPublished
Publication dates
Online21 Aug 2015
Publication process dates
Accepted19 Jul 2015
PublisherPublic Library of Science, San Fancisco (PLOS)
Public Library of Science (PLOS)
Copyright licenseCC BY
ISSN1932-6203

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