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other·ophthalmology, cornea, preclinical research, biomedical research, infectious disease·PMC10637725

The Aspergillus fumigatus UPR is variably activated across nutrient and host environments and is critical for the establishment of corneal infection

PLOS Pathogens · 12 authors, 4 centres

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TL;DR

The study used a mouse model and in vitro experiments to show that the unfolded protein response (UPR) in the fungus Aspergillus fumigatus is required for causing corneal infection, but its activation varies between different host tissues and nutrient conditions.

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This study investigated the role of the unfolded protein response (UPR) in Aspergillus fumigatus pathogenesis. Researchers used genetic deletion of the key UPR regulator hacA (ΔhacA) and found it was avirulent in a mouse model of fungal keratitis. Transcriptomic analysis of wild-type and ΔhacA strains under low, medium, and high ER stress conditions revealed distinct HacA-dependent gene expression profiles in each environment. The findings suggest the fungal UPR is a tunable pathway critical for adaptation to different environments and a potential antifungal target.

STUDY TYPE

other

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ophthalmology

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ORIGINAL PAPER

PMC10637725

The Aspergillus fumigatus UPR is variably activated across nutrient and host environments and is critical for the establishment of corneal infection

PLOS Pathogens

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ABSTRACT

The Aspergillus fumigatus unfolded protein response (UPR) is a two-component relay consisting of the ER-bound IreA protein, which splices and activates the mRNA of the transcription factor HacA. Spliced hacA accumulates under conditions of acute ER stress in vitro , and UPR null mutants are hypovirulent in a murine model of invasive pulmonary infection. In this report, we demonstrate that a hacA deletion mutant ( ΔhacA ) is furthermore avirulent in a model of fungal keratitis, a corneal infection, and an important cause of ocular morbidity and unilateral blindness worldwide. Interestingly, we demonstrate that A . fumigatus hacA is spliced in infected lung samples, but not in the cornea, suggesting the amount of ER stress experienced by the fungus varies upon the host niche. To better understand how the UPR contributes to fungal cell biology across a spectrum of ER-stress levels, we employed transcriptomics on the wild-type and ΔhacA strains in glucose minimal media (low stress), glucose minimal media with dithiothreitol (high stress), and gelatin minimal media as a proxy for the nutrient stress encountered in the cornea (mid-level stress). These data altogether reveal a unique HacA-dependent transcriptome under each condition, suggesting that HacA activity is finely-tuned and required for proper fungal adaptation in each environment. Taken together, our results indicate that the fungal UPR could serve as an important antifungal target in the setting of both invasive pulmonary and corneal infections.

CITATION EXPORT

Manali M. Kamath, Jorge D. Lightfoot, Emily M. Adams et al.. The Aspergillus fumigatus UPR is variably activated across nutrient and host environments and is critical for the establishment of corneal infection. PLOS Pathogens. (2023). https://doi.org/10.1371/journal.ppat.1011435

AUTHORS

12 · 4 CENTRES

Manali M. Kamath, Jorge D. Lightfoot, Emily M. Adams, Ryan M. Kiser, Becca L. Wells, Kevin K. Fuller, Alex Andrianopoulos, Robert A. Cramer, Alex Andrianopoulos, Robert A. Cramer, Alex Andrianopoulos, Robert A. Cramer

1 Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
2 Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
3 Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
Geisel School of Medicine at Dartmouth, UNITED STATES

EDITOR / REVIEWER

Robert A. Cramer