The Aspergillus fumigatus sitA Phosphatase Homologue Is Important for Adhesion, Cell Wall Integrity, Biofilm Formation, and Virulence.
Aspergillus fumigatus is an opportunistic pathogenic fungus able to infect immunocompromised patients, eventually causing disseminated infections that are difficult to control and lead to high mortality rates. It is important to understand how the signaling pathways that regulate these factors involved in virulence are orchestrated. Protein phosphatases are central to numerous signal transduction pathways. Here, we characterize the A. fumigatus protein phosphatase 2A SitA, the Saccharomyces cerevisiae Sit4p homologue. The sitA gene is not an essential gene, and we were able to construct an A. fumigatus null mutant. The ΔsitA strain had decreased MpkA phosphorylation levels, was more sensitive to cell wall-damaging agents, had increased β-(1,3)-glucan and chitin, was impaired in biofilm formation, and had decreased protein kinase C activity. The ΔsitA strain is more sensitive to several metals and ions, such as MnCl2, CaCl2, and LiCl, but it is more resistant to ZnSO4. The ΔsitA strain was avirulent in a murine model of invasive pulmonary aspergillosis and induces an augmented tumor necrosis factor alpha (TNF-α) response in mouse macrophages. These results stress the importance of A. fumigatus SitA as a possible modulator of PkcA/MpkA activity and its involvement in the cell wall integrity pathway.
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Vinícius Leite Pedro
VL
Bom
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Patrícia Alves
PA
de Castro
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Lizziane K
LK
Winkelströter
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Marçal
M
Marine
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Juliana I
JI
Hori
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Leandra Naira Zambelli
LN
Ramalho
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Thaila Fernanda
TF
dos Reis
Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Maria Helena S
MH
Goldman
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Neil Andrew
NA
Brown
Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, The University of Glasgow, Glasgow, United Kingdom.
Ranjith
R
Rajendran
Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, The University of Glasgow, Glasgow, United Kingdom.
Gordon
G
Ramage
School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
Louise A
LA
Walker
School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
Carol A
CA
Munro
Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Paulo, Brazil.
Marina Campos
MC
Rocha
Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Paulo, Brazil.
Iran
I
Malavazi
Medical Mycology Research Center, Chiba University, Chiba, Japan.
Daisuke
D
Hagiwara
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil National Laboratory of Science and Technology of Bioethanol (CTBE), Campinas, Brazil ggoldman@usp.br.
Gustavo H
GH
Goldman
D000818:Animals; D001232:Aspergillus fumigatus / Q000378:metabolism*; D018441:Biofilms / Q000254:growth & development*; D027682:Cation Transport Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002473:Cell Wall / Q000378:metabolism*; D002686:Chitin / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005656:Fungal Proteins / Q000378:metabolism; D055744:Invasive Pulmonary Aspergillosis / Q000378:metabolism / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014774:Virulence / Q000502:physiology*
D027682:Cation Transport Proteins; D005656:Fungal Proteins; D014409:Tumor Necrosis Factor-alpha; D002686:Chitin; D010744:Phosphoric Monoester Hydrolases