Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance

Autoři: Patrícia Alves de Castro aff001;  Ana Cristina Colabardini aff001;  Adriana Oliveira Manfiolli aff001;  Jéssica Chiaratto aff001;  Lilian Pereira Silva aff001;  Eliciane Cevolani Mattos aff001;  Giuseppe Palmisano aff002;  Fausto Almeida aff003;  Gabriela Felix Persinoti aff004;  Laure Nicolas Annick Ries aff003;  Laura Mellado aff001;  Marina Campos Rocha aff005;  Michael Bromley aff006;  Roberto Nascimento Silva aff003;  Gabriel Scalini de Souza aff007;  Flávio Vieira Loures aff007;  Iran Malavazi aff005;  Neil Andrew Brown aff008;  Gustavo H. Goldman aff001
Působiště autorů: Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil aff001;  Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil aff002;  Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil aff003;  Laboratório Nacional de Biorrenováveis (LNBR), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, São Paulo, Brasil aff004;  Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil aff005;  Manchester Fungal Infection Group, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom aff006;  Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, São José dos Campos, Brazil aff007;  Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, United Kingdom aff008
Vyšlo v časopise: Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. PLoS Genet 15(12): e1008551. doi:10.1371/journal.pgen.1008551
Kategorie: Research Article


Aspergillus fumigatus causes invasive aspergillosis, the most common life-threatening fungal disease of immuno-compromised humans. The treatment of disseminated infections with antifungal drugs, including echinocandin cell wall biosynthesis inhibitors, is increasingly challenging due to the rise of drug-resistant pathogens. The fungal calcium responsive calcineurin-CrzA pathway influences cell morphology, cell wall composition, virulence, and echinocandin resistance. A screen of 395 A. fumigatus transcription factor mutants identified nine transcription factors important to calcium stress tolerance, including CrzA and ZipD. Here, comparative transcriptomics revealed CrzA and ZipD regulated the expression of shared and unique gene networks, suggesting they participate in both converged and distinct stress response mechanisms. CrzA and ZipD additively promoted calcium stress tolerance. However, ZipD also regulated cell wall organization, osmotic stress tolerance and echinocandin resistance. The absence of ZipD in A. fumigatus caused a significant virulence reduction in immunodeficient and immunocompetent mice. The ΔzipD mutant displayed altered cell wall organization and composition, while being more susceptible to macrophage killing and eliciting an increased pro-inflammatory cytokine response. A higher number of neutrophils, macrophages and activated macrophages were found in ΔzipD infected mice lungs. Collectively, this shows that ZipD-mediated regulation of the fungal cell wall contributes to the evasion of pro-inflammatory responses and tolerance of echinocandin antifungals, and in turn promoting virulence and complicating treatment options.

Klíčová slova:

Aspergillus fumigatus – Calcium signaling – Cell walls – Gene expression – Mouse models – Osmotic shock – Phosphatases – Transcription factors


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