Imperial College London

DrRachelEdgar

Faculty of MedicineDepartment of Infectious Disease

Sir Henry Dale Fellow
 
 
 
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Contact

 

rachel.edgar Website

 
 
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Location

 

11Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

20 results found

Styles CT, Zhou J, Flight KE, Brown JC, Lewis C, Wang X, Vanden Oever M, Peacock TP, Wang Z, Millns R, O'Neill JS, Borodavka A, Grove J, Barclay WS, Tregoning JS, Edgar RSet al., 2023, Propylene glycol inactivates respiratory viruses and prevents airborne transmission, EMBO Molecular Medicine, Vol: 15, ISSN: 1757-4676

Viruses are vulnerable as they transmit between hosts, and we aimed to exploit this critical window. We found that the ubiquitous, safe, inexpensive and biodegradable small molecule propylene glycol (PG) has robust virucidal activity. Propylene glycol rapidly inactivates a broad range of viruses including influenza A, SARS-CoV-2 and rotavirus and reduces disease burden in mice when administered intranasally at concentrations commonly found in nasal sprays. Most critically, vaporised PG efficiently abolishes influenza A virus and SARS-CoV-2 infectivity within airborne droplets, potently preventing infection at levels well below those tolerated by mammals. We present PG vapour as a first-in-class non-toxic airborne virucide that can prevent transmission of existing and emergent viral pathogens, with clear and immediate implications for public health.

Journal article

Watson JL, Seinkmane E, Styles CT, Mihut A, Krüger LK, McNally KE, Planelles-Herrero VJ, Dudek M, McCall PM, Barbiero S, Vanden Oever M, Peak-Chew SY, Porebski BT, Zeng A, Rzechorzek NM, Wong DCS, Beale AD, Stangherlin A, Riggi M, Iwasa J, Morf J, Miliotis C, Guna A, Inglis AJ, Brugués J, Voorhees RM, Chambers JE, Meng Q-J, O'Neill JS, Edgar RS, Derivery Eet al., 2023, Macromolecular condensation buffers intracellular water potential, Nature, Vol: 623, Pages: 842-852, ISSN: 0028-0836

Optimum protein function and biochemical activity critically depends on water availability because solvent thermodynamics drive protein folding and macromolecular interactions1. Reciprocally, macromolecules restrict the movement of 'structured' water molecules within their hydration layers, reducing the available 'free' bulk solvent and therefore the total thermodynamic potential energy of water, or water potential. Here, within concentrated macromolecular solutions such as the cytosol, we found that modest changes in temperature greatly affect the water potential, and are counteracted by opposing changes in osmotic strength. This duality of temperature and osmotic strength enables simple manipulations of solvent thermodynamics to prevent cell death after extreme cold or heat shock. Physiologically, cells must sustain their activity against fluctuating temperature, pressure and osmotic strength, which impact water availability within seconds. Yet, established mechanisms of water homeostasis act over much slower timescales2,3; we therefore postulated the existence of a rapid compensatory response. We find that this function is performed by water potential-driven changes in macromolecular assembly, particularly biomolecular condensation of intrinsically disordered proteins. The formation and dissolution of biomolecular condensates liberates and captures free water, respectively, quickly counteracting thermal or osmotic perturbations of water potential, which is consequently robustly buffered in the cytoplasm. Our results indicate that biomolecular condensation constitutes an intrinsic biophysical feedback response that rapidly compensates for intracellular osmotic and thermal fluctuations. We suggest that preserving water availability within the concentrated cytosol is an overlooked evolutionary driver of protein (dis)order and function.

Journal article

Beale AD, Hayter EA, Crosby P, Valekunja UK, Edgar RS, Chesham JE, Maywood ES, Labeed FH, Reddy AB, Wright Jr KP, Lilley KS, Bechtold DA, Hastings MH, O'Neill JSet al., 2023, Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells, The EMBO Journal, Vol: 42, ISSN: 0261-4189

Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

Journal article

Zhuang X, Edgar RS, McKeating JA, 2022, The role of circadian clock pathways in viral replication, Springer Seminars in Immunopathology, Vol: 44, Pages: 175-182, ISSN: 1863-2297

The daily oscillations of bi ological and behavioural processes are controlled by the circadian clock circuitry that drives the physiology of the organism and, in particular, the functioning of the immune system in response to infectious agents. Circadian rhythmicity is known to affect both the pharmacokinetics and pharmacodynamics of pharmacological agents and vaccine-elicited immune responses. A better understanding of the role circadian pathways play in the regulation of virus replication will impact our clinical management of these diseases. This review summarises the experimental and clinical evidence on the interplay between different viral pathogens and our biological clocks, emphasising the importance of continuing research on the role played by the biological clock in virus-host organism interaction.

Journal article

O'Neill JS, Hoyle NP, Robertson JB, Edgar RS, Beale AD, Peak-Chew SY, Day J, Costa ASH, Frezza C, Causton HCet al., 2021, Author Correction: Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis., Nature Communications, Vol: 12, Pages: 7269-7269, ISSN: 2041-1723

Journal article

Wong DCS, Seinkmane E, Zeng A, Stangherlin A, Rzechorzek NM, Beale AD, Day J, Reed M, Peak-Chew SY, Styles CT, Edgar RS, Putker M, O'Neill JSet al., 2021, CRYPTOCHROMES promote daily protein homeostasis, The EMBO Journal, Vol: 41, Pages: 1-23, ISSN: 0261-4189

The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild-type and CRY-deficient fibroblasts under constant conditions. In CRY-deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild-type controls. Most strikingly, the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY-deficient cells. This proteome imbalance in CRY-deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide-ranging phenotypes of CRY-deficient mice. Rather than generating large-scale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post-translational functions of CRY proteins ultimately act to maintain protein and osmotic homeostasis against daily perturbation.

Journal article

Stangherlin A, Watson JL, Wong DCS, Barbiero S, Zeng A, Seinkmane E, Chew SP, Beale AD, Hayter EA, Guna A, Inglis AJ, Putker M, Bartolami E, Matile S, Lequeux N, Pons T, Day J, van Ooijen G, Voorhees RM, Bechtold DA, Derivery E, Edgar RS, Newham P, O'Neill JSet al., 2021, Publisher Correction: Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology., Nature Communications, Vol: 12, Pages: 6988-6988, ISSN: 2041-1723

Journal article

Stangherlin A, Watson JL, Wong DCS, Barbiero S, Zeng A, Seinkmane E, Chew SP, Beale AD, Hayter EA, Guna A, Inglis AJ, Putker M, Bartolami E, Matile S, Lequeux N, Pons T, Day J, van Ooijen G, Voorhees RM, Bechtold DA, Derivery E, Edgar RS, Newham P, O'Neill JSet al., 2021, Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology, Nature Communications, Vol: 12, Pages: 1-14, ISSN: 2041-1723

Between 6–20% of the cellular proteome is under circadian control and tunes mammalian cell function with daily environmental cycles. For cell viability, and to maintain volume within narrow limits, the daily variation in osmotic potential exerted by changes in the soluble proteome must be counterbalanced. The mechanisms and consequences of this osmotic compensation have not been investigated before. In cultured cells and in tissue we find that compensation involves electroneutral active transport of Na+, K+, and Cl− through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes confer daily variation in electrical activity. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes.

Journal article

Putker M, Wong DCS, Seinkmane E, Rzechorzek NM, Zeng A, Hoyle NP, Chesham JE, Edwards MD, Feeney KA, Fischer R, Peschel N, Chen K-F, Vanden Oever M, Edgar RS, Selby CP, Sancar A, O'Neill JSet al., 2021, CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping, The EMBO Journal, Vol: 40, Pages: 1-15, ISSN: 0261-4189

Circadian rhythms are a pervasive property of mammalian cells, tissues and behaviour, ensuring physiological adaptation to solar time. Models of cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are therefore considered essential components of the cellular clock mechanism, supported by behavioural arrhythmicity of CRY‐deficient (CKO) mice under constant conditions. Challenging this interpretation, we find locomotor rhythms in adult CKO mice under specific environmental conditions and circadian rhythms in cellular PER2 levels when CRY is absent. CRY‐less oscillations are variable in their expression and have shorter periods than wild‐type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and period determination by CK1δ/ε activity to be maintained. In the absence of CRY‐mediated feedback repression and rhythmic Per2 transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post‐translational.

Journal article

Styles C, Oever MV, Brown J, Rai S, Walsh S, Ryan F, Barclay W, Edgar Ret al., 2021, Treatment of irritant contact dermatitis in healthcare settings during the COVID19 pandemic: The emollient Dermol 500 exhibits virucidal activity against influenza A virus and SARS-CoV-2, Publisher: Cold Spring Harbor Laboratory

Objectives To investigate whether the antimicrobial emollient Dermol 500 and its active components, benzalkonium chloride (BAK) and chlorohexidine dihydrochloride (CD), exhibit virucidal activity thus informing whether Dermol 500 is a suitable soap substitute for use during the COVID19 pandemic, to combat the increased incidence of work-related contact dermatitis in clinical settings that we report here.Methods Inactivation of influenza A virus and SARS-CoV-2 by Dermol 500 and the independent and combined virucidal activity of the Dermol 500 components BAK and CD was assessed by influenza A virus and SARS-CoV-2 infectivity assays. Viruses were treated with concentrations of BAK and CD comparable to Dermol 500, and lower, and infectivity of the viruses assessed by titration.Results Dermol 500 exhibits comparable virucidal activity to alcohol-based sanitisers against influenza A virus and SARS-CoV-2. In addition, the Dermol 500 components BAK and CD exhibit independent and synergistic virucidal activity against influenza A virus and SARS-CoV-2, the causative agent of COVID19.Conclusions The synergistic virucidal activity of the Dermol 500 components BAK and CD makes Dermol 500 suitable as a soap substitute to treat and prevent work-related contact dermatitis in healthcare settings.

Working paper

O' Neill JS, Hoyle NP, Robertson JB, Edgar RS, Beale AD, Peak-Chew SY, Day J, Costa ASH, Frezza C, Causton HCet al., 2020, Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis, Nature Communications, Vol: 11, Pages: 1-11, ISSN: 2041-1723

Yeast physiology is temporally regulated, this becomes apparent under nutrient-limited conditions and results in respiratory oscillations (YROs). YROs share features with circadian rhythms and interact with, but are independent of, the cell division cycle. Here, we show that YROs minimise energy expenditure by restricting protein synthesis until sufficient resources are stored, while maintaining osmotic homeostasis and protein quality control. Although nutrient supply is constant, cells sequester and store metabolic resources via increased transport, autophagy and biomolecular condensation. Replete stores trigger increased H+ export which stimulates TORC1 and liberates proteasomes, ribosomes, chaperones and metabolic enzymes from non-membrane bound compartments. This facilitates translational bursting, liquidation of storage carbohydrates, increased ATP turnover, and the export of osmolytes. We propose that dynamic regulation of ion transport and metabolic plasticity are required to maintain osmotic and protein homeostasis during remodelling of eukaryotic proteomes, and that bioenergetic constraints selected for temporal organisation that promotes oscillatory behaviour.

Journal article

Lasselin J, Ingre M, Regenbogen C, Olsson MJ, Garke M, Brytting M, Edgar R, Lekander M, Axelsson Jet al., 2019, Sleep during naturally occurring respiratory infections: A pilot study, Brain, Behavior, and Immunity, Vol: 79, Pages: 236-243, ISSN: 0889-1591

Journal article

Henslee EA, Crosby P, Kitcatt SJ, Parry JSW, Bernardini A, Abdallat RG, Braun G, Fatoyinbo HO, Harrison EJ, Edgar RS, Hoettges KF, Reddy AB, Jabr RI, von Schantz M, O'Neill JS, Labeed FHet al., 2017, Rhythmic potassium transport regulates the circadian clock in human red blood cells, Nature Communications, Vol: 8, Pages: 1978-1978, ISSN: 2041-1723

Circadian rhythms organize many aspects of cell biology and physiology to a daily temporal program that depends on clock gene expression cycles in most mammalian cell types. However, circadian rhythms are also observed in isolated mammalian red blood cells (RBCs), which lack nuclei, suggesting the existence of post-translational cellular clock mechanisms in these cells. Here we show using electrophysiological and pharmacological approaches that human RBCs display circadian regulation of membrane conductance and cytoplasmic conductivity that depends on the cycling of cytoplasmic K+ levels. Using pharmacological intervention and ion replacement, we show that inhibition of K+ transport abolishes RBC electrophysiological rhythms. Our results suggest that in the absence of conventional transcription cycles, RBCs maintain a circadian rhythm in membrane electrophysiology through dynamic regulation of K+ transport.

Journal article

Edgar RS, Stangherlin A, Nagy AD, Nicoll MP, Efstathiou S, O'Neill JS, Reddy ABet al., 2016, Cell autonomous regulation of herpes and influenza virus infection by the circadian clock, Proceedings of the National Academy of Sciences, Vol: 113, Pages: 10085-10090, ISSN: 0027-8424

Viruses are intracellular pathogens that hijack host cell machinery and resources to replicate. Rather than being constant, host physiology is rhythmic, undergoing circadian (∼24 h) oscillations in many virus-relevant pathways, but whether daily rhythms impact on viral replication is unknown. We find that the time of day of host infection regulates virus progression in live mice and individual cells. Furthermore, we demonstrate that herpes and influenza A virus infections are enhanced when host circadian rhythms are abolished by disrupting the key clock gene transcription factor Bmal1. Intracellular trafficking, biosynthetic processes, protein synthesis, and chromatin assembly all contribute to circadian regulation of virus infection. Moreover, herpesviruses differentially target components of the molecular circadian clockwork. Our work demonstrates that viruses exploit the clockwork for their own gain and that the clock represents a novel target for modulating viral replication that extends beyond any single family of these ubiquitous pathogens.

Journal article

Milev NB, Rey G, Valekunja UK, Edgar RS, O'Neill JS, Reddy ABet al., 2015, Analysis of the Redox Oscillations in the Circadian Clockwork, CIRCADIAN RHYTHMS AND BIOLOGICAL CLOCKS, PT B, Vol: 552, Pages: 185-210, ISSN: 0076-6879

Journal article

Valekunja UK, Edgar RS, Oklejewicz M, van der Horst GTJ, O'Neill JS, Tamanini F, Turner DJ, Reddy ABet al., 2013, Histone methyltransferase MLL3 contributes to genome-scale circadian transcription, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 1554-1559, ISSN: 0027-8424

Journal article

Olmedo M, O'Neill JS, Edgar RS, Valekunja UK, Reddy AB, Merrow Met al., 2012, Circadian regulation of olfaction and an evolutionarily conserved, nontranscriptional marker in <i>Caenorhabditis elegans</i>, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 20479-20484, ISSN: 0027-8424

Journal article

Edgar RS, Green EW, Zhao Y, van Ooijen G, Olmedo M, Qin X, Xu Y, Pan M, Valekunja UK, Feeney KA, Maywood ES, Hastings MH, Baliga NS, Merrow M, Millar AJ, Johnson CH, Kyriacou CP, O'Neill JS, Reddy ABet al., 2012, Peroxiredoxins are conserved markers of circadian rhythms, Nature, Vol: 485, Pages: 459-U65, ISSN: 0028-0836

Cellular life emerged ∼3.7 billion years ago. With scant exception, terrestrial organisms have evolved under predictable daily cycles owing to the Earth’s rotation. The advantage conferred on organisms that anticipate such environmental cycles has driven the evolution of endogenous circadian rhythms that tune internal physiology to external conditions. The molecular phylogeny of mechanisms driving these rhythms has been difficult to dissect because identified clock genes and proteins are not conserved across the domains of life: Bacteria, Archaea and Eukaryota. Here we show that oxidation–reduction cycles of peroxiredoxin proteins constitute a universal marker for circadian rhythms in all domains of life, by characterizing their oscillations in a variety of model organisms. Furthermore, we explore the interconnectivity between these metabolic cycles and transcription–translation feedback loops of the clockwork in each system. Our results suggest an intimate co-evolution of cellular timekeeping with redox homeostatic mechanisms after the Great Oxidation Event ∼2.5 billion years ago.

Journal article

Gill MB, Edgar R, May JS, Stevenson PGet al., 2008, A Gamma-Herpesvirus Glycoprotein Complex Manipulates Actin to Promote Viral Spread, PLOS ONE, Vol: 3, ISSN: 1932-6203

Journal article

Jones DC, Edgar RS, Ahmad T, Cummings JRF, Jewell DP, Trowsdale J, Young NTet al., 2006, Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility, GENES AND IMMUNITY, Vol: 7, Pages: 576-582, ISSN: 1466-4879

Journal article

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