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

English version

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
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1008551

Souhrn

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:

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

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