The Heat Shock Transcription Factor HsfA Is Essential for Thermotolerance and Regulates Cell Wall Integrity in Aspergillus fumigatus

Author(s)

Fabri, Joao Henrique Tadini Marilhano ^[1] ; Rocha, Marina Campos ^[1] ; Fernandes, Caroline Mota ^[2] ; Persinoti, Gabriela Felix ^[3] ; Ries, Laure Nicolas Annick ^[4] ; da Cunha, Anderson Ferreira ^[1] ; Goldman, Gustavo Henrique ^[5] ; Del Poeta, Maurizio ^{[6, 7, 2, 8]} ; Malavazi, Iran ^[1]

Affiliation

^[1] Univ Fed Sao Carlos, Dept Genet & Evolucao, Ctr Ciencias Biol & Saude, Sao Carlos - Brazil

^[2] SUNY Stony Brook, Dept Microbiol & Immunol, Stony Brook, NY 11794 - USA

^[3] Ctr Nacl Pesquisa Energia & Mat CNPEM, Lab Nacl Biorrenovaveis LNBR, Campinas, SP - Brazil

^[4] Univ Exeter, MRC Ctr Med Mycol, Exeter, Devon - England

^[5] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Sao Paulo - Brazil

^[6] SUNY Stony Brook, Sch Med, Div Infect Dis, Stony Brook, NY 11794 - USA

^[7] SUNY Stony Brook, Inst Chem Biol & Drug Discovery, Stony Brook, NY 11794 - USA

^[8] Vet Adm Med Ctr, Northport, NY 11768 - USA

• Document type: Journal article
• Source: FRONTIERS IN MICROBIOLOGY; v. 12, APR 9 2021.
• Web of Science Citations: 0

Abstract

The deleterious effects of human-induced climate change have long been predicted. However, the imminent emergence and spread of new diseases, including fungal infections through the rise of thermotolerant strains, is still neglected, despite being a potential consequence of global warming. Thermotolerance is a remarkable virulence attribute of the mold Aspergillus fumigatus. Under high-temperature stress, opportunistic fungal pathogens deploy an adaptive mechanism known as heat shock (HS) response controlled by heat shock transcription factors (HSFs). In eukaryotes, HSFs regulate the expression of several heat shock proteins (HSPs), such as the chaperone Hsp90, which is part of the cellular program for heat adaptation and a direct target of HSFs. We recently observed that the perturbation in cell wall integrity (CWI) causes concomitant susceptibility to elevated temperatures in A. fumigatus, although the mechanisms underpinning the HS response and CWI cross talking are not elucidated. Here, we aim at further deciphering the interplay between HS and CWI. Our results show that cell wall ultrastructure is severely modified when A. fumigatus is exposed to HS. We identify the transcription factor HsfA as essential for A. fumigatus viability, thermotolerance, and CWI. Indeed, HS and cell wall stress trigger the coordinated expression of both hsfA and hsp90. Furthermore, the CWI signaling pathway components PkcA and MpkA were shown to be important for HsfA and Hsp90 expression in the A. fumigatus biofilms. Lastly, RNA-sequencing confirmed that hsfA regulates the expression of genes related to the HS response, cell wall biosynthesis and remodeling, and lipid homeostasis. Our studies collectively demonstrate the connection between the HS and the CWI pathway, with HsfA playing a crucial role in this cross-pathway regulation, reinforcing the importance of the cell wall in A. fumigatus thermophily. (AU)

• FAPESP's process: 17/19694-3 - The role of heat shock proteins HsfA and Hsp90 and the regulator SmiA at cell wall integrity pathway activity in the opportunistic human pathogen Aspergillus fumigatus
• Grantee: Iran Malavazi
• Support Opportunities: Regular Research Grants
• 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 Opportunities: Research Projects - Thematic Grants