title: The Aspergillus pH-responsive transcription factor PacC regulates virulence.
abstract: The ability of a pathogen to adapt to the host environment is usually required for the initiation of disease. Here we have investigated the importance of the Aspergillus nidulans PacC-mediated pH response in the pathogenesis of pulmonary aspergillosis. Using mutational analysis, we demonstrate that, in neutropenic mice, elimination of the A. nidulans pH-responsive transcription factor PacC, blocking the ambient pH signal transduction pathway or prevention of PacC proteolytic processing acutely attenuates virulence. Infections caused by these alkali-sensitive mutants are characterized by limited growth in vivo and a reduction of inflammatory cell infiltration. In stark contrast, constitutive activation of PacC causes increased mortality marked by extensive fungal invasive growth. PacC action is therefore required for, and able to enhance virulence, demonstrating that the A. nidulans pH-responsive transcription factor PacC plays a pivotal role in pulmonary pathogenesis.
authors.affiliation: Department of Infectious Diseases, Imperial College London, London W12 0NN, UK. e.bignell@imperial.ac.uk
authors.forename: Elaine
authors.initials: E
authors.lastname: Bignell
authors.forename: Susana
authors.initials: S
authors.lastname: Negrete-Urtasun
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Calcagno
authors.forename: Ken
authors.initials: K
authors.lastname: Haynes
authors.forename: Herbert N
authors.initials: HN
authors.lastname: Arst
authors.forename: Tom
authors.initials: T
authors.lastname: Rogers
mesh_terms: D001233:Aspergillus nidulans / Q000254:growth & development / Q000472:pathogenicity / Q000502:physiology*; D001483:Base Sequence; D017931:DNA Primers; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D016681:Genome, Fungal; D005838:Genotype; D006863:Hydrogen-Ion Concentration; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D016335:Zinc Fingers
chemical_list: D017931:DNA Primers; D005656:Fungal Proteins; C092394:PacC protein, Aspergillus; D014157:Transcription Factors