Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels

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Thinking strategically about assessment

Drawing upon the literature on strategy formulation in organisations, this paper argues for a focus on strategy as process. It relates this to the need to think strategically about assessment, a need engendered by resource pressures, developments in learning and the demands of external stakeholders. It is argued that in practice assessment strategies are often formed at the level of practice, but that this produces contradiction and confusion at higher levels. Such tensions cannot be managed away, but they can be reflected on and mitigated. The paper suggests a framework for the construction of assessment strategies at different levels of an institution. However, the main conclusion is that the process of constructing such strategies should be an opportunity for learning and reflection, rather than one of compliance

Fungal Chitin Dampens Inflammation through IL-10 Induction Mediated by NOD2 and TLR9 Activation

Funding: JW and NARG thank the Wellcome Trust (080088, 086827, 075470), The Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377) and the European Union ALLFUN (FP7/2007 2013, HEALTH-2010-260338) for funding. MGN was supported by a Vici grant of the Netherlands Organisation for Scientific Research. AJPB and DMM were funded by STRIFE, ERC-2009-AdG-249793 and AJPB additionally by FINSysB, PITN-GA-2008-214004 and the BBSRC [BB/F00513X/1]. MDL was supported by the MRC (MR/J008230/1). GDB and SV were funded by the Wellcome Trust (086558) and TB and MK were funded by the Deutsche Forschungsgemeinschaft (Bi 696/3-1; Bi 696/5-2; Bi 696/10-1). MS was supported by the Deutsche Forschungsgemeinschaft (Sch 897/1-3) and the National Institute of Dental and Craniofacial Research (R01 DE017514-01). TDK and RKSM were funded by the National Institute of Health (AR056296, AI101935) and the American Lebanese Syrian Associated Charities (ALSAC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Background Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylateinhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. Conclusions/Significance These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents

Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors

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Recognition and blocking of innate immunity cells by Candida albicans chitin

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Non-canonical signalling mediates changes in fungal cell wall PAMPs that drive immune evasion

Data Availability The authors declare that the data supporting the findings of this study are available within the paper (and its supplementary information files). Acknowledgements We are grateful to Raif Yuecel, Linda Duncan, Kimberley Sim and Ailsa Laird in the Iain Fraser Cytometry Centre, and to Kevin MacKenzie, Debbie Wilkinson, Gillian Milne and Lucy Wight in our Microscopy and Histology Core Facility for their superb support. We thank Katja Schafer and Angela Lopez for help with the design of primers and for providing CRISPR-Cas9 protocols for mutant construction. We also thank our colleagues in the Candida community, and in particular Jan Quinn, Guanghua Huang, Suzanne Noble, Karl Kuchler, Patrick van Dijck, Rich Calderone and Malcolm Whiteway for providing strains used in this study. This work was funded by a programme grant from the UK Medical Research Council [www.mrc.ac.uk: MR/M026663/1], and by PhD studentships from the University of Aberdeen to AP, DL. The work was also supported by the Medical Research Council Centre for Medical Mycology and the University of Aberdeen [MR/N006364/1], by the European Commission [FunHoMic: H2020-MSCA-ITN-2018-812969], and by the Wellcome Trust via Investigator, Collaborative, Equipment, Strategic and Biomedical Resource awards [www.wellcome.ac.uk: 075470, 086827, 093378, 097377, 099197, 101873, 102705, 200208]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Hypoxia Promotes Immune Evasion by Triggering β-glucan Masking on the Candida albicans Cell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling

We are very grateful to the members of our Iain Fraser Cytometry Centre and Microscopy and Histology Core Facility for their superb help, advice and support. We also thank our generous colleagues in the Candida community, and in particular Ana Traven, Jan Quinn, Guanghua Huang, Suzanne Noble, Donna MacCallum, Liz Johnson, Karl Kuchler, Patrick van Dijck, Rich Calderone and Malcolm Whiteway for providing strains used in this study. This work was funded by grants from the UK Medical Research Council [www.mrc.ac.uk], to AJPB, NARG, LPE, MN (MR/M026663/1), and by PhD studentships from the University of Aberdeen to AP, DL. The work was also supported by the Wellcome Trust [www.wellcome.ac.uk], NARG, GDB, AJPB (097377) and GDB (102705); and by the Medical Research Council Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

The carboxylic acid transporters Jen1 and Jen2 affect the architecture and fluconazole susceptibility of Candida albicans biofilm in the presence of lactate

Candida albicans has the ability to adapt to different host niches, often glucose-limited but rich in alternative carbon sources. In these glucose-poor microenvironments, this pathogen expresses JEN1 and JEN2 genes, encoding carboxylate transporters, which are important in the early stages of infection. This work investigated how host microenvironments, in particular acidic containing lactic acid, affect C. albicans biofilm formation and antifungal drug resistance. Multiple components of the extracellular matrix were also analysed, including their impact on antifungal drug resistance, and the involvement of both Jen1 and Jen2 in this process. The results show that growth on lactate affects biofilm formation, morphology and susceptibility to fluconazole and that both Jen1 and Jen2 might play a role in these processes. These results support the view that the adaptation of Candida cells to the carbon source present in the host niches affects their pathogenicity.This study was funded by the Portuguese Foundation for Science and Technology (FCT) [grant number PTDC/BIAMIC/5184/2014]. SM, CFR and RA received FCT PhD studentships [grant numbers SFRH/BD/74790/2010, SFRH/ BD/93078/2013, PD/BD/113813/2015, respectively]. The work on CBMA was supported by FCT [grant number UID/ BIA/04050/2013] and COMPETE 2020 [grant number POCI01-0145-FEDER-007569]. The work on CEB was supported by FCT [grant number UID/BIO/04469/2013], COMPETE 2020 [grant number POCI-01-0145-FEDER-006684] and BioTecNorte operation [grant number NORTE-01-0145FEDER-000004] funded by the ERDF under the scope of Norte2020 – Programa Operacional Regional do Norte. AJPB was funded by the UK Medical Research Council [grant number MR/M026663/1]; by the UK Biotechnology and Biological Research Council [grant number BB/K017365/1]; and by the MRC Centre for Medical Mycology and the University of Aberdeen [grant number MR/M026663/1]. The funders had no role in study design, data collection and analysis, the decision to publish, or in the preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Immune cells fold and damage fungal hyphae

Acknowledgements We thank Ben Rutter and Alex Brand for providing Mycelia sterilia hyphae, and Gillian Griffiths for insightful advice. We are grateful to the Microscopy and Histology Core Facility at the University of Aberdeen for their help, advice and support. This work was funded by grants from the UK Medical Research Council [www.mrc.ac.uk], to AJPB, NARG, LPE, MN (MR/M026663/1, MR/M026663/2), and from the University of Aberdeen to AP, DL. The work was also supported by Wellcome [www.wellcome.ac.uk]: NARG, GDB, AJPB (097377); NARG (101873, 200208); and GDB (102705). Further support for this work was also provided by the Medical Research Council Centre for Medical Mycology (MR/N006364/1). MGN was supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD