Thoughts on the evolution of Core Environmental Responses in yeasts

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordThe model yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe, display Core Environmental Responses (CERs) that include the induction of a core set of stress genes in response to diverse environmental stresses. CERs underlie the phenomenon of stress cross-protection, whereby exposure to one type of stress can provide protection against subsequent exposure to a second type of stress. CERs have probably arisen through the accumulation, over evolutionary time, of protective anticipatory responses (“adaptive prediction”). CERs have been observed in other evolutionarily divergent fungi but, interestingly, not in the pathogenic yeast, Candida albicans. We argue that this is because we have not looked in the right place. In response to specific host inputs, C. albicans does activate anticipatory responses that protect it against impending attack from the immune system. Therefore, we suggest that C. albicans has evolved a CER that reflects the environmental challenges it faces in host niches.Medical Research Council (MRC)MRC Centre for Medical Mycology, University of ExeterUniversity of AberdeenWellcome Trus

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

This is the final version. Available from the publisher via the DOI in this record.To colonise their host, pathogens must counter local environmental and immunological challenges. Here, we reveal that the fungal pathogen Candida albicans exploits diverse host-associated signals to promote immune evasion by masking of a major pathogen-associated molecular pattern (PAMP), β-glucan. Certain nutrients, stresses and antifungal drugs trigger β-glucan masking, whereas other inputs, such as nitrogen sources and quorum sensing molecules, exert limited effects on this PAMP. In particular, iron limitation triggers substantial changes in the cell wall that reduce β-glucan exposure. This correlates with reduced phagocytosis by macrophages and attenuated cytokine responses by peripheral blood mononuclear cells. Iron limitation-induced β-glucan masking depends on parallel signalling via the iron transceptor Ftr1 and the iron-responsive transcription factor Sef1, and the protein kinase A pathway. Our data reveal that C. albicans exploits a diverse range of specific host signals to trigger protective anticipatory responses against impending phagocytic attack and promote host colonisation.Medical Research Council (MRC)European CommissionWellcome Trus

Anticipatory Stress Responses and Immune Evasion in Fungal Pathogens

This is the final version. Available on open access from Cell Press via the DOI in this recordIn certain niches, microbes encounter environmental challenges that are temporally linked. In such cases, microbial fitness is enhanced by the evolution of anticipatory responses where the initial challenge simultaneously activates pre-emptive protection against the second impending challenge. The accumulation of anticipatory responses in domesticated yeasts, which have been termed 'adaptive prediction', has led to the emergence of 'core stress responses' that provide stress cross-protection. Protective anticipatory responses also seem to be common in fungal pathogens of humans. These responses reflect the selective pressures that these fungi have faced relatively recently in their evolutionary history. Consequently, some pathogens have evolved 'core environmental responses' which exploit host signals to trigger immune evasion strategies that protect them against imminent immune attack.Medical Research Council (MRC)University of AberdeenUniversity of Exete

Brachyury identifies a class of enteroendocrine cells in normal human intestinal crypts and colorectal cancer

Normal homeostasis of adult intestinal epithelium and repair following tissue damage is maintained by a balance of stem and differentiated cells, many of which are still only poorly characterised. Enteroendocrine cells of the gut are a small population of differentiated, secretory cells that are critical for integrating nutrient sensing with metabolic responses, dispersed amongst other epithelial cells. Recent evidence suggests that sub-sets of secretory enteroendocrine cells can act as reserve stem cells. Given the link between cells with stem-like properties and cancer, it is important that we identify factors that might provide a bridge between the two. Here, we identify a sub-set of chromogranin A-positive enteroendocrine cells that are positive for the developmental and cancer-associated transcription factor Brachyury in normal human small intestinal and colonic crypts. Whilst chromogranin A-positive enteroendocrine cells are also Brachyury-positive in colorectal tumours, expression of Brachyury becomes more diffuse in these samples, suggesting a more widespread function in cancer. The finding of the developmental transcription factor Brachyury in normal adult human intestinal crypts may extend the functional complexity of enteroendocrine cells and serves as a platform for assessment of the molecular processes of intestinal homeostasis that underpins our understanding of human health, cancer and aging.The authors would like to thank the following organisations for supporting this work: J. Jezkova, R.J. McFarlane & J.A. Wakeman are supported by Cancer Research Wales; J.S. Williams is supported by Coleg Cymraeg Cenedlaethol; J. Sammut and R.J. McFarlane are supported by NWCR (grant no. CR950); S. Gollins is supported by National Institute for Social Care and Health Research Academic Health Science Collaboration (NISCHR AHSC) Clinical Research Fellow. F.Pinto is supported by Fundação para a Ciência e Tecnologia (FCT; grant no. SFRH/BD/81369/2011). R.M. Reis is recipient of a Brazilian National Counsel of Technological and Scientific Development (CNPq) scholarship. Geraint Williams is supported by the Wales Gene Park. are supported by NWCR (grant no. CR950); S. Gollins is supported by National Institute for Social Care and Health Research Academic Health Science Collaboration (NISCHR AHSC) Clinical Research Fellow. F.Pinto is supported by Fundação para a Ciência e Tecnologia (FCT; grant no. SFRH/BD/81369/2011). R.M. Reis is recipient of a Brazilian National Counsel of Technological and Scientific Development (CNPq) scholarship. Geraint Williams is supported by the Wales Gene Park.info:eu-repo/semantics/publishedVersio

IRF7-Associated Immunophenotypes Have Dichotomous Responses to Virus/Allergen Coexposure and OM-85-Induced Reprogramming

High risk for virus-induced asthma exacerbations in children is associated with an IRF7lo immunophenotype, but the underlying mechanisms are unclear. Here, we applied a Systems Biology approach to an animal model comprising rat strains manifesting high (BN) versus low susceptibility (PVG) to experimental asthma, induced by virus/allergen coexposure, to elucidate the mechanism(s)-of-action of the high-risk asthma immunophenotype. We also investigated potential risk mitigation via pretreatment with the immune training agent OM-85. Virus/allergen coexposure in low-risk PVG rats resulted in rapid and transient airways inflammation alongside IRF7 gene network formation. In contrast, responses in high-risk BN rats were characterized by severe airways eosinophilia and exaggerated proinflammatory responses that failed to resolve, and complete absence of IRF7 gene networks. OM-85 had more profound effects in high-risk BN rats, inducing immune-related gene expression changes in lung at baseline and reducing exaggerated airway inflammatory responses to virus/allergen coexposure. In low-risk PVG rats, OM-85 boosted IRF7 gene networks in the lung but did not alter baseline gene expression or cellular influx. Distinct IRF7-associated asthma risk immunophenotypes have dichotomous responses to virus/allergen coexposure and respond differentially to OM-85 pretreatment. Extrapolating to humans, our findings suggest that the beneficial effects OM-85 pretreatment may preferentially target those in high-risk subgroups

Impact of secreted glucanases upon the cell surface and fitness of Candida albicans during colonisation and infection.

Acknowledgements We thank Raif Yuecel and Attila Bebes in the Exeter Centre for Cytomics for their help with the cytometry, and Annie Phillips-Brookes, Jamie Harvey and the BSU staff for their support with the animal experimentation. We are grateful to Karen Moore, Paul O’Neill and Jemima Onime in the University of Exeter Sequencing Facility University of Exeter Sequencing Facility for their help with the barcode sequencing. We also thank Paulina Cherek in the Bioimaging Facility in Exeter Biosciences for her help with the transmission electron microscopy, and Darren Thomson in the MRC Centre for Medical Mycology for his support for our the DeltaVision imaging. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewe

Glucose-enhanced oxidative stress resistance-A protective anticipatory response that enhances the fitness of Candida albicans during systemic infection

Acknowledgments We thank Carol Munro for her generosity in providing the plasmids for barcoding C. albicans, and Victoria Brown, Gerry Fink, Bill Fonzi, Guanghua Huang, Joachim Morschauser, Suzanne Noble, Jesus Pla, Patrick Van Dijck, Reinhard Würzner and Oscar Zaragoza for providing strains. We thank our colleagues in the MRC Centre for Medical Mycology and the Aberdeen Fungal Group for insightful discussions. We are grateful to the following Research Facilities for their advice and support: the Centre for Genome Enabled Biology at the University of Aberdeen, and the Sequencing Facility at the University of Exeter for help with the barcode sequencing. Funding: This work was funded by a programme grant to AJPB, NARG, LEP and MGN from the UK Medical Research Council [www.mrc.ac.uk: MR/M026663/1, MR/M026663/2] and by PhD studentships to DEL from the Universities of Aberdeen and Exeter. The work was also supported by the Medical Research Council Centre for Medical Mycology (MR/N006364/1, MR/N006364/2). NARG acknowledges Wellcome support of Senior Investigator (101873/Z/13/Z, 224323/Z/21/Z) and Collaborative (200208/A/15/Z, 215599/Z/19/Z) Awards. MGN was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. The barcode sequencing performed by the Exeter Sequencing Facility utilised equipment funded by Wellcome (218247/Z/19/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Nature of b-1,3-Glucan-Exposing Features on Candida albicans Cell Wall and Their Modulation

Funding Information: This work was supported by a programme grant from the UK Medical Research Council (MR/M026663/1; MR/M026663/2) and by the Medical Research Council Centre for Medical Mycology (MR/N006364/1; MR/N006364/2). NARG acknowledges Wellcome support for a Senior Investigator (101873/Z/13/Z), Collaborative (200208/A/15/Z; 215599/Z/19/Z) and Strategic Awards (097377/Z11/Z). MGN was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research.Peer reviewedPublisher PD

Further investigation of confirmed urinary tract infection (UTI) in children under five years: a systematic review.

Background: Further investigation of confirmed UTI in children aims to prevent renal scarring and future complications. Methods: We conducted a systematic review to determine the most effective approach to the further investigation of confirmed urinary tract infection (UTI) in children under five years of age. Results: 73 studies were included. Many studies had methodological limitations or were poorly reported. Effectiveness of further investigations: One study found that routine imaging did not lead to a reduction in recurrent UTIs or renal scarring. Diagnostic accuracy: The studies do not support the use of less invasive tests such as ultrasound as an alternative to renal scintigraphy, either to rule out infection of the upper urinary tract (LR- = 0.57, 95%CI: 0.47, 0.68) and thus to exclude patients from further investigation or to detect renal scarring (LR+ = 3.5, 95% CI: 2.5, 4.8). None of the tests investigated can accurately predict the development of renal scarring. The available evidence supports the consideration of contrast-enhanced ultrasound techniques for detecting vesico-ureteric reflux (VUR), as an alternative to micturating cystourethrography (MCUG) (LR+ = 14.1, 95% CI: 9.5, 20.8; LR- = 0.20, 95%CI: 0.13, 0.29); these techniques have the advantage of not requiring exposure to ionising radiation. Conclusion: There is no evidence to support the clinical effectiveness of routine investigation of children with confirmed UTI. Primary research on the effectiveness, in terms of improved patient outcome, of testing at all stages in the investigation of confirmed urinary tract infection is urgently required

A CO2 sensing module modulates β-1,3-glucan exposure in Candida albicans.

This work was funded by a program grant to A.J.P.B., N.A.R.G., L.P.E., and M.G.N. from the UK Medical Research Council [www.mrc.ac.uk: MR/M026663/1, MR/M026663/2]. The work was also supported by the Medical Research Council Centre for Medical Mycology [MR/N006364/1, MR/N006364/2], by a grant to C.d.E. from 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, 217163, 224323]. Work in the d’Enfert laboratory was supported by grants from the Agence Nationale de Recherche (ANR-10-LABX-62-IBEID) and the Swiss National Science Foundation (Sinergia CRSII5_173863/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD