Caspofungin Treatment of Aspergillus fumigatus Results in ChsG-Dependent Upregulation of Chitin Synthesis and the Formation of Chitin-Rich Microcolonies

Date of Acceptance: 23/07/2015 We thank Gillian Milne for help with electron microscopy, Sophie M. Schäfer for pilot experiments, and Emilia Mellado for strains. All authors acknowledge financial support of Gilead Sciences through Ph.D. studentships for L.A.W. and K.K.L. We also acknowledge research grants from the Wellcome Trust (080088, 086827, 075470, 099215, and 097377) and the British Society for Antimicrobial Chemotherapy.Peer reviewedPublisher PD

Titan cell production in Cryptococcus neoformans reshapes the cell wall and capsule composition during infection

This work was supported by the National Institutes of Health (R01AI080275 and R21AI22352), the NIH Fogarty International Center (R25TW009345), the University of Minnesota Center for Translational Science Institute (UL1TR000114), Wellcome Trust (086827, 075470, 097377, 101873 & 200208) and MRC Centre for Medical Mycology (N006364/1). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.Peer reviewedPublisher PD

Anti-Candida targets and cytotoxicity of casuarinin isolated from Plinia cauliflora leaves in a bioactivity-guided study

Peer reviewedPublisher PD

Yeast species-specific, differential inhibition of β-1,3-glucan synthesis by poacic acid and caspofungin

We sincerely thank Jeff Piotrowski and John Ralph for providing poacic acid, and David Perlin for providing C. glabrata fks1Δ and fks2Δ mutant strains and clinical isolates (DPL series) for this study. We thank Carol Munro, Sam Miller and Louise Walker for helpful discussions; and Raif Yuecel, Attila Bebes, and Linda Duncan in the Iain Fraser Cytometry Centre (IFCC) for FACS, and Kevin MacKenzie, Debbie Wilkinson, Gillian Milne, and Lucy Wright for microscopy at the University of Aberdeen core facilities. This work was supported by the Wellcome Trust (101873, 086827, 075470, & 200208) and MRC Centre for Medical Mycology (N006364/1), and Grants-in-Aid for Scientific Research from the Ministry of Education Culture, Sports, Science and Technology, Japan (24370002 and 15H04402 to Y.O.).Peer reviewedPublisher PD

The protein kinase Ire1 impacts pathogenicity of Candida albicans by regulating homeostatic adaptation to endoplasmic reticulum stress

Funding Information: The authors thank Aaron P. Mitchell for providing strains and plasmids. The authors also thank all Panwar lab members for critical reading of the manuscript. Funding support from the Defence Research and Development Organization (LSRB‐358/SH&DD/2019) to S.L.P. is acknowledged. Additional funding from SERB, Department of Science and Technology, Government of India, under the umbrella project DST‐PURSE as well as Capacity Build‐up, UGC‐Resource Networking and UGC‐SAP awarded to Jawaharlal Nehru University is also acknowledged. S.S. acknowledges Junior and Senior Research Fellowships (UGC‐JRF/SRF) from the University Grant Commission (UGC) and SRF from the Indian Council for Medical Research (ICMR). Support from the Kamangar family in the form of an endowed chair to C.J.N., National Institutes of Health (NIH) grant R35GM124594 to C.J.N., PGC2018‐095047‐B‐I00 and InGEMICS‐CM S2017/BMD3691/Comunidad Autonoma de Madrid to J.P. and Wellcome as a Senior Investigator Award (101873/Z/13/Z), Collaborative Award (200208/A/15/Z) and Strategic Award (097377/Z11/Z) by the MRC Centre for Medical Mycology (MR/N006364/2) to N.A.R.G. is acknowledged. Publisher Copyright: © 2021 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved.Peer reviewedPublisher PD

Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans

Funding Information: We thank Carol Munro for helpful discussions during the research, Raif Yuecel, Elizabeth Adams, Linda Duncan, Barry Lewis and Kimberley Sim for assistance with FACS at Aberdeen Cytometry Core Facility, and Yang Meng and Dominique Sanglard with help in construction of mutants. We also thank Linghuo Jiang, David Soll, Jes?s Pla, Jan Quinn, Terry Roemer and Joseph Heitman for mutant strains. N.A.R.G. acknowledges support from the Wellcome Trust [Senior Investigator (101873/Z/13/Z), Collaborative (200208/A/15/Z and 215599/Z/19/Z) and Strategic (097377/Z11/Z) Awards] and from the Medical Research Council Centre for Medical Mycology (MR/N006364/2). This work was also supported by a Marie Curie FP7-PEOPLE-ITN-2008 grant (MB004 RGE0655 ARIADNE) and by a Wellcome Trust project grant (086827). Open access funding provided by University of Exeter. Deposited in PMC for immediate release.Peer reviewedPublisher PD

Elevated catalase expression in a fungal pathogen is a double-edged sword of iron

We thank our colleagues in the Aberdeen Fungal Group, Lloyd Peck (British Antarctic Survey) and John Helmann (Cornell University) for insightful discussions. We thank Christophe d’Enfert and Melanie Legrand (Institut Pasteur) for help with the design of barcodes and provision of the CIp10-PTET-GTw overexpression vector and CEC2908 strain. We are grateful to the following Core Facilities at the University of Aberdeen for their excellent technical assistance, advice and support: the Medical Research Facility; the Centre for Genome Enabled Biology and Medicine; the Iain Fraser Cytometry Centre; the Microscopy and Histology Facility; Aberdeen Proteomics; and the qPCR Facility.Peer reviewedPublisher PD

Cell Wall Remodeling Enzymes Modulate Fungal Cell Wall Elasticity and Osmotic Stress Resistance

International audienceThe fungal cell wall confers cell morphology and protection against environmental insults. For fungal pathogens, the cell wall is a key immunological modulator and an ideal therapeutic target. Yeast cell walls possess an inner matrix of interlinked-glucan and chitin that is thought to provide tensile strength and rigidity. Yeast cells remodel their walls over time in response to environmental change, a process controlled by evolutionarily conserved stress (Hog1) and cell integrity (Mkc1, Cek1) signal-ing pathways. These mitogen-activated protein kinase (MAPK) pathways modulate cell wall gene expression, leading to the construction of a new, modified cell wall. We show that the cell wall is not rigid but elastic, displaying rapid structural realignments that impact survival following osmotic shock. Lactate-grown Candida albicans cells are more resistant to hyperosmotic shock than glucose-grown cells. We show that this elevated resistance is not dependent on Hog1 or Mkc1 signaling and that most cell death occurs within 10 min of osmotic shock. Sudden decreases in cell volume drive rapid increases in cell wall thickness. The elevated stress resistance of lactate-grown cells correlates with reduced cell wall elasticity, reflected in slower changes in cell volume following hyperosmotic shock. The cell wall elasticity of lactate-grown cells is increased by a triple mutation that inactivates the Crh family of cell wall cross-linking enzymes, leading to increased sensitivity to hyperosmotic shock. Overexpressing Crh family members in glucose-grown cells reduces cell wall elasticity, providing partial protection against hyperosmotic shock. These changes correlate with structural realignment of the cell wall and with the ability of cells to withstand osmotic shock

The protein kinase Ire1 impacts pathogenicity of Candida albicans by regulating homeostatic adaptation to endoplasmic reticulum stress.

The unfolded protein response (UPR), crucial for the maintenance of endoplasmic reticulum (ER) homeostasis, is tied to the regulation of multiple cellular processes in pathogenic fungi. Here, we show that Candida albicans relies on an ER-resident protein, inositol-requiring enzyme 1 (Ire1) for sensing ER stress and activating the UPR. Compromised Ire1 function impacts cellular processes that are dependent on functional secretory homeostasis, as inferred from transcriptional profiling. Concordantly, an Ire1-mutant strain exhibits pleiotropic roles in ER stress response, antifungal tolerance, cell wall regulation and virulence-related traits. Hac1 is the downstream target of C. albicans Ire1 as it initiates the unconventional splicing of the 19 bp intron from HAC1 mRNA during tunicamycin-induced ER stress. Ire1 also activates the UPR in response to perturbations in cell wall integrity and cell membrane homeostasis in a manner that does not necessitate the splicing of HAC1 mRNA. Furthermore, the Ire1-mutant strain is severely defective in hyphal morphogenesis and biofilm formation as well as in establishing a successful infection in vivo. Together, these findings demonstrate that C. albicans Ire1 functions to regulate traits that are essential for virulence and suggest its importance in responding to multiple stresses, thus integrating various stress signals to maintain ER homeostasis