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.
Highlights
Fungal human diseases and their impacts on human health and world economy have frequently been overlooked (Brown et al, 2012)
Our previous results indicated that the A. fumigatus cell wall integrity (CWI) pathway mutants are less tolerant to heat shock (HS) and PkcA signaling is required for early adaptation to HS (Rocha et al, 2020b)
These results suggest that the sudden increase in temperature triggers the cell wall remodeling, indicating that this structure is highly dynamic and responsive to fluctuations in the surrounding temperature, potentially underlying a survival mechanism to counteract HS represented by the dramatic expansion of the cell wall
Summary
Fungal human diseases and their impacts on human health and world economy have frequently been overlooked (Brown et al, 2012). It has been proposed that global warming may significantly enhance the adaptation of fungal populations to higher temperatures, which may cause the emergence of new fungal diseases associated with difficult treatment (Garcia-Solache and Casadevall, 2010; Casadevall et al, 2019) In this worrisome scenario, the saprophytic mold and opportunistic human pathogen Aspergillus fumigatus stands out for its intrinsic thermophilic and thermotolerance traits and the rise of resistant isolates to available antifungal drugs (van Paassen et al, 2016). These attributes of A. fumigatus biology help to explain its high prevalence in the environment and support the thermotolerance as an essential determinant for its pathogenicity since it allows the adaptation of the fungus to temperatures found before and after the infection of mammalian host and favors the persistence of this fungus inside the human lungs (Albrecht et al, 2010; Haas et al, 2016)
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