A role for the unfolded protein response (UPR) in virulence and antifungal susceptibility in Aspergillus fumigatus

Daryl L. Richie, Lukas Hartl, Vishukumar Aimanianda, Michael S. Winters, Kevin K. Fuller, Michael D. Miley, Stephanie White, Jason W. McCarthy, Jean Paul Latgé, Marta Feldmesser, Judith C. Rhodes, David S. Askew

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Filamentous fungi rely heavily on the secretory pathway, both for the delivery of cell wall components to the hyphal tip and the production and secretion of extracellular hydrolytic enzymes needed to support growth on polymeric substrates. Increased demand on the secretory system exerts stress on the endoplasmic reticulum (ER), which is countered by the activation of a coordinated stress response pathway termed the unfolded protein response (UPR). To determine the contribution of the UPR to the growth and virulence of the filamentous fungal pathogen Aspergillus fumigatus, we disrupted the hacA gene, encoding the major transcriptional regulator of the UPR. The ΔhacA mutant was unable to activate the UPR in response to ER stress and was hypersensitive to agents that disrupt ER homeostasis or the cell wall. Failure to induce the UPR did not affect radial growth on rich medium at 37°C, but cell wall integrity was disrupted at 45°C, resulting in a dramatic loss in viability. The ΔhacA mutant displayed a reduced capacity for protease secretion and was growth-impaired when challenged to assimilate nutrients from complex substrates. In addition, the ΔhacA mutant exhibited increased susceptibility to current antifungal agents that disrupt the membrane or cell wall and had attenuated virulence in multiple mouse models of invasive aspergillosis. These results demonstrate the importance of ER homeostasis to the growth and virulence of A. fumigatus and suggest that targeting the UPR, either alone or in combination with other antifungal drugs, would be an effective antifungal strategy.

Original languageEnglish (US)
Article numbere1000258
JournalPLoS Pathogens
Volume5
Issue number1
DOIs
StatePublished - Jan 2009

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Unfolded Protein Response
Aspergillus fumigatus
Virulence
Cell Wall
Growth
Endoplasmic Reticulum Stress
Endoplasmic Reticulum
Homeostasis
Aspergillosis
Antifungal Agents
Secretory Pathway
Cellular Structures
Peptide Hydrolases
Fungi
Food
Membranes
Enzymes
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Richie, D. L., Hartl, L., Aimanianda, V., Winters, M. S., Fuller, K. K., Miley, M. D., ... Askew, D. S. (2009). A role for the unfolded protein response (UPR) in virulence and antifungal susceptibility in Aspergillus fumigatus. PLoS Pathogens, 5(1), [e1000258]. https://doi.org/10.1371/journal.ppat.1000258

A role for the unfolded protein response (UPR) in virulence and antifungal susceptibility in Aspergillus fumigatus. / Richie, Daryl L.; Hartl, Lukas; Aimanianda, Vishukumar; Winters, Michael S.; Fuller, Kevin K.; Miley, Michael D.; White, Stephanie; McCarthy, Jason W.; Latgé, Jean Paul; Feldmesser, Marta; Rhodes, Judith C.; Askew, David S.

In: PLoS Pathogens, Vol. 5, No. 1, e1000258, 01.2009.

Research output: Contribution to journalArticle

Richie, DL, Hartl, L, Aimanianda, V, Winters, MS, Fuller, KK, Miley, MD, White, S, McCarthy, JW, Latgé, JP, Feldmesser, M, Rhodes, JC & Askew, DS 2009, 'A role for the unfolded protein response (UPR) in virulence and antifungal susceptibility in Aspergillus fumigatus', PLoS Pathogens, vol. 5, no. 1, e1000258. https://doi.org/10.1371/journal.ppat.1000258
Richie, Daryl L. ; Hartl, Lukas ; Aimanianda, Vishukumar ; Winters, Michael S. ; Fuller, Kevin K. ; Miley, Michael D. ; White, Stephanie ; McCarthy, Jason W. ; Latgé, Jean Paul ; Feldmesser, Marta ; Rhodes, Judith C. ; Askew, David S. / A role for the unfolded protein response (UPR) in virulence and antifungal susceptibility in Aspergillus fumigatus. In: PLoS Pathogens. 2009 ; Vol. 5, No. 1.
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