Rachael Coyle

Wellcome Sanger Institute

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i-10 index

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Co-Authors

Theo Sanderson

The Francis Crick Institute

Lisa Verzier

Harvard University

Julian C. Rayner

University of Cambridge

Lee M

Wellcome Sanger Institute

Abbie L. A. Binch

Sheffield Hallam University

Christine L. Le Maitre

University of Sheffield

Theodoros I. Roumeliotis

Institute of Cancer Research

Julia Steinberg

University of Sydney

Eleftheria Zeggini

Helmholtz Zentrum München

Mercedes Pardo

Institute of Cancer Research

Cooperative Institutions

Wellcome Sanger Institute

University of Cape Town

University of Sheffield

Virginia Tech

South African Medical Research Council

University of Cambridge

Royal Hallamshire Hospital

Universitat de Barcelona

Wellcome Trust

Columbia University Irving Medical Center

Author Statistics

Papers

Citation

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2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Plasmodium falciparum Phosphatidylinositol-4-kinase and Hemozoin Formation with In Vivo Efficacy

Journal of Medicinal Chemistry (2024)

Godwin Akpeko Dziwornu Donald Seanego Stephen Fienberg Monica Clements Jasmin Ferreira

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of

Hemozoin

10.1021/acs.jmedchem.4c01154

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Citations (4)

YAT2150 is irresistible in Plasmodium falciparum and active against Plasmodium vivax and Leishmania clinical isolates

Scientific Reports (2025)

Inés Bouzón‐Arnáiz Mukul Rawat Rachael Coyle Lionel Brice Feufack-Donfack Malen Ea

Plasmodium (life cycle)

10.1038/s41598-025-85346-y

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Citations (0)

UsingPlasmodium knowlesias a model for screeningPlasmodium vivaxblood-stage malaria vaccine targets reveals new candidates

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Duncan Ndungu Ndegwa Jessica B. Hostetler Alejandro Marín-Menéndez Theo Sanderson Kioko Mwikali

ABSTRACT Plasmodium vivax is responsible for the majority of malaria cases outside Africa. Unlike P. falciparum , the P. vivax life-cycle includes a dormant liver stage, the hypnozoite, which can cause infection in the absence of mosquito transmission. An effective vaccine against P. vivax blood stages would limit symptoms and pathology from such recurrent infections, and therefore could play a critical role in the control of this species. Vaccine development in P. vivax , however, lags considerably behind P. falciparum , which has many identified targets with several having transitioned to Phase II testing. By contrast only one P. vivax blood-stage vaccine candidate based on the Duffy Binding Protein (PvDBP), has reached Phase Ia, in large part because the lack of a continuous in vitro culture system for P. vivax limits systematic screening of new candidates. We used the close phylogenetic relationship between P. vivax and P. knowlesi , for which an in vitro culture system in human erythrocytes exists, to test the scalability of systematic reverse vaccinology to identify and prioritise P. vivax blood-stage targets. A panel of P. vivax proteins predicted to function in erythrocyte invasion were expressed as full-length recombinant ectodomains in a mammalian expression system. Eight of these antigens were used to generate polyclonal antibodies, which were screened for their ability to recognize orthologous proteins in P. knowlesi . These antibodies were then tested for inhibition of growth and invasion of both wild type P. knowlesi and chimeric P. knowlesi lines modified using CRISPR/Cas9 to exchange P. knowlesi genes with their P. vivax orthologues. Candidates that induced antibodies that inhibited invasion to a similar level as PvDBP were identified, confirming the utility of P. knowlesi as a model for P. vivax vaccine development and prioritizing antigens for further follow up. AUTHOR SUMMARY Malaria parasites cause disease after invading human red blood cells, implying that a vaccine that interrupts this process could play a significant role in malaria control. Multiple Plasmodium parasite species can cause malaria in humans, and most malaria outside Africa is caused by Plasmodium vivax . There is currently no effective vaccine against the blood stage of any malaria parasite, and progress in P. vivax vaccine development has been particularly hampered because this parasite species cannot be cultured for prolonged periods of time in the lab. We explored whether a related species, P. knowlesi , which can be propagated in human red blood cells in vitro , can be used to screen for potential P. vivax vaccine targets. We raised antibodies against selected P. vivax proteins and testedtheir ability to recognize and prevent P. knowlesi parasites from invading human red blood cells, thereby identifying multiple novel vaccine candidates.

Plasmodium knowlesi

Reverse vaccinology

Polyclonal antibodies

10.1101/2020.08.07.241125

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Plasmodium knowlesi as a model system for characterising Plasmodium vivax drug resistance candidate genes

PLoS neglected tropical diseases (2019)

Lisa Verzier Rachael Coyle Shivani Singh Theo Sanderson Julian C. Rayner

Plasmodium vivax causes the majority of malaria outside Africa, but is poorly understood at a cellular level partly due to technical difficulties in maintaining it in in vitro culture conditions. In the past decades, drug resistant P. vivax parasites have emerged, mainly in Southeast Asia, but while some molecular markers of resistance have been identified, none have so far been confirmed experimentally, which limits interpretation of the markers, and hence our ability to monitor and control the spread of resistance. Some of these potential markers have been identified through P. vivax genome-wide population genetic analyses, which highlighted genes under recent evolutionary selection in Southeast Asia, where chloroquine resistance is most prevalent. These genes could be involved in drug resistance, but no experimental proof currently exists to support this hypothesis. In this study, we used Plasmodium knowlesi, the most closely related species to P. vivax that can be cultured in human erythrocytes, as a model system to express P. vivax genes and test for their role in drug resistance. We adopted a strategy of episomal expression, and were able to express fourteen P. vivax genes, including two allelic variants of several hypothetical resistance genes. Their expression level and localisation were assessed, confirming cellular locations conjectured from orthologous species, and suggesting locations for several previously unlocalised proteins, including an apical location for PVX_101445. These findings establish P. knowlesi as a suitable model for P. vivax protein expression. We performed chloroquine and mefloquine drug assays, finding no significant differences in drug sensitivity: these results could be due to technical issues, or could indicate that these genes are not actually involved in drug resistance, despite being under positive selection pressure in Southeast Asia. These data confirm that in vitro P. knowlesi is a useful tool for studying P. vivax biology. Its close evolutionary relationship to P. vivax, high transfection efficiency, and the availability of markers for colocalisation, all make it a powerful model system. Our study is the first of its kind using P. knowlesi to study unknown P. vivax proteins and investigate drug resistance mechanisms.

Plasmodium knowlesi

10.1371/journal.pntd.0007470

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Citations (21)

Influence of washing and quenching in profiling the metabolome of adherent mammalian cells: a case study with the metastatic breast cancer cell line MDA-MB-231

The Analyst (2017)

Rahul Vijay Kapoore Rachael Coyle Carolyn A. Staton Nicola J. Brown Seetharaman Vaidyanathan

1 step of PBS wash followed by quenching with 60% methanol supplemented with 70 mM HEPES results in minimal metabolite leakage.

Metabolome

Metabolite profiling

HEPES

Leakage (economics)

10.1039/c7an00207f

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Citations (43)

Cell line dependence of metabolite leakage in metabolome analyses of adherent normal and cancer cell lines

Metabolomics (2015)

Rahul Vijay Kapoore Rachael Coyle Carolyn A. Staton Nicola J. Brown Seetharaman Vaidyanathan

Metabolome

Trypsinization

10.1007/s11306-015-0833-4

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Citations (29)

Immunoblotting of Plasmodium blood stage proteins v1

Lisa Verzier Rachael Coyle Julian C. Rayner

This protocol was developed to study protein expression in Plasmodium red blood stage. Large multispanning membrane proteins, such as pvmdr1 (PVX_080100), could be extracted and detected using this method.

Plasmodium (life cycle)

10.17504/protocols.io.wuefete

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Citations (1)

Investigation of the Role of Copy Number Variation In the Pathogenesis of Type 1 Von Willebrand Disease

Blood (2010)

Daniel J. Hampshire Lisa D.S. Bloomer Ahlam Al-buhairan Rachael Coyle Raymon Vijzelaar

von Willebrand Disease

Pathogenesis

10.1182/blood.v116.21.2218.2218

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Citations (1)

A novel chemogenomic screening platform for scalable antimalarial drug target identification

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Christopher Bower-Lepts Mukul Rawat William Collins Keith Gareth Girling Madeline R. Luth

Summary Large-scale chemical-genetic screening, or chemogenomics, can faciliate rapid and scalable drug target identification. To establish a chemogenomic screen for antimalarial drug target identification, we leveraged ∼600 Plasmodium berghei artificial chromosomes (PbACs) encoding potential drug targets to generate a systematic overexpression library. PbACs were engineered with DNA barcodes, enabling their quantification within mixed pools using next generation sequencing (barcode sequencing or BarSeq). Pooled transfection of PbACs into the highly genetically tractable Plasmodium knowlesi demonstrated efficient vector uptake and transcription of encoded P. berghei genes. Parasite pools were exposed to antimalarial candidates, with pilot screens probing for known gene-compound associations identifying their targets with high sensitivity. Screening antimalarial inhibitors with unknown mechanisms of action successfully identified pi4k as the target for one novel compound, which was subsequently validated using in vitro evolution in Plasmodium falciparum parasites. This sensitive and scalable chemogenomics platform therefore represents a valuable early-stage tool for antimalarial target identification.

Identification

Drug target

10.1101/2024.08.27.609875

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Citations (0)

Alpha-synuclein is increased in erythrocytes in Parkinson’s Disease cases

Research Square (Research Square) (2024)

Rachael Coyle Anne M. Roberts Malcolm Horne Christopher Fowler Colin L. Masters

Abstract Idiopathic Parkinson’s disease (iPD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD). Mutations in the SCNA gene, which encodes the protein alpha synuclein (α-syn), are associated with familial forms of Parkinson's disease (PD). Additionally, Lewy bodies (LBs) rich in α-synuclein are a hallmark of idiopathic Parkinson's disease (iPD) pathology. Unlike AD, there are no effective blood-based diagnostic assays for iPD. Recent studies show that measures of misfolded α-syn in cerebrospinal fluid (CSF) and skin biopsies reflect the diagnosis of iPD. The presence of misfolded α-syn suggests that the altered cellular processes in the brain that lead to aggregated α-syn may also occur in the periphery. However, CSF and skin biopsies are intrusive, highlighting the need for a blood-based diagnostic assay. Erythrocytes are the richest source of α-syn in the body, and we hypothesized that peripheral α-syn changes could be detected in erythrocytes in iPD. To test this hypothesis, we used a targeted liquid chromatography-mass spectrometry (LC-MS) assay, that included ¹⁵N-enriched recombinant α-syn as an internal standard. We compared the levels of α-syn in erythrocytes from iPD patients, AD patients, and healthy controls (CN). α-syn concentrations were significantly elevated in iPD (48.1 (29.7) µg*mL^-1 of erythrocytes, median (IQR)) compared to CN (36.1 (28.4) µg*mL^-1) and no difference was observed in AD (33.5 (18.1) µg*mL^-1). Although α-syn levels were significantly elevated in iPD, the receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.62, indicating that erythrocytic α-syn levels alone are not sufficient for diagnostic purposes.

Lewy body

Pathogenesis

10.21203/rs.3.rs-5375389/v1

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Citations (0)