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

Author(s):Show less -

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]

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

• 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 - The role of mitogen-activated protein kinase (MPKA) MpkA in regulating gliotoxin production in Aspergillus fumigatus.
• 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