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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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de Castro, Patricia Alves [1] ; Colabardini, Ana Cristina [1] ; Manfiolli, Adriana Oliveira [1] ; Chiaratto, Jessica [1] ; Silva, Lilian Pereira [1] ; Mattos, Eliciane Cevolani [1] ; Palmisano, Giuseppe [2] ; Almeida, Fausto [3] ; Persinoti, Gabriela Felix [4] ; Annick Ries, Laure Nicolas [3] ; Mellado, Laura [1] ; Rocha, Marina Campos [5] ; Bromley, Michael [6] ; Silva, Roberto Nascimento [3] ; de Souza, Gabriel Scalini [7] ; Loures, Flavio Vieira [7] ; Malavazi, Iran [5] ; Brown, Neil Andrew [8] ; Goldman, Gustavo H. [1]
Total Authors: 19
Affiliation:
[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias Farmaceut, Ribeirao Preto - Brazil
[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Sao Paulo - Brazil
[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ribeirao Preto - Brazil
[4] CNPEM, Lab Nacl Biorrenovaveis LNBR, Campinas, SP - Brazil
[5] Univ Fed Sao Carlos, Ctr Ciencias Biol & Sande, Dept Genet & Evolucao, Sao Carlos, SP - Brazil
[6] Univ Manchester, Inst Inflammat & Repair, Manchester Fungal Infect Grp, Manchester, Lancs - England
[7] Univ Fed Sao Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos - Brazil
[8] Univ Bath, Dept Biol & Biochem, Bath, Avon - England
Total Affiliations: 8
Document type: Journal article
Source: PLOS GENETICS; v. 15, n. 12 DEC 2019.
Web of Science Citations: 0
Abstract

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 Delta zipD 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 Delta zipD 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. (AU)

FAPESP's process: 17/07536-4 - Molecular mechanisms involved in paradoxal growth induced by caspofungin in Aspergillus fumigatus
Grantee:Ana Cristina Colabardini
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 16/21392-2 - "characterization of transcription factors that have the basic domain" zipper "leucine (bZIP) ATF1 in Aspergillus fumigatus"
Grantee:Lilian Pereira Silva
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 14/06863-3 - Post-translational modifications in cancer and parasite infection diagnosis: methodological approaches and biological implications
Grantee:Giuseppe Palmisano
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 16/12948-7 - Functional characterization of the Aspergillus fumigatus bZIP ZipD transcription factor
Grantee:Patrícia Alves de Castro Silva
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 16/07870-9 - The influence of mitogen activated protein kinases (MAPK) on the expression of genetic determinants important for Aspergillus fumigatus virulence
Grantee:Gustavo Henrique Goldman
Support type: Research Projects - Thematic Grants
FAPESP's process: 16/22062-6 - Molecular characterization of htlA and fhdA transcription factors of human pathogenic fungus Aspergillus fumigatus
Grantee:Jéssica Chiaratto
Support type: Scholarships in Brazil - Master
FAPESP's process: 14/04783-2 - Study of the plasmacytoid and myeloid dendritic cells function during Paracoccidioides brasiliensis infection
Grantee:Flávio Vieira Loures
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 17/19288-5 - Characterization of MAPKs dependent-phosphoproteomes of Aspergillus fumigatus under stress conditions
Grantee:Eliciane Cevolani Mattos
Support type: Scholarships in Brazil - Post-Doctorate