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The role of malaria in the outcome and treatment of Ebola virus disease

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  • Full or part time
    Prof Julian Hiscox
    Prof L Renia
  • Application Deadline
    No more applications being accepted

Project Description

This project presents a unique opportunity to study in both the UK and Singapore focusing on two high consequence infections: Ebola virus and malaria and the synergy between them.

The 2013–2016 Ebola virus (EBOV) crisis in West Africa devastated the health care and wider infrastructures of many communities. The outbreak was unprecedented in scale, providing an opportunity for an in-depth analysis of infected humans and observations of previously unknown aspects of EBOV biology. The epidemic occurred at a time when high-resolution genomic analysis could be used to analyze samples obtained from patients during the outbreak.

Many of the patients from West Africa who had Ebola virus disease (EVD) would have had an underlying burden of infectious disease. Additionally, during an EVD breakout, other infections may be present and/or translocate from one organ to another, complicating disease and patient management and influencing infection outcome. Guinea, where the 2013–2016 outbreak originated, experiences high levels of malaria transmission (>1 case per 1,000 population), with Plasmodium falciparum being responsible for the majority of cases.
This project focuses on the hypothesis that infection with Plasmodium falciparum, the causative agent of malaria, negatively influences the outcome of Ebola virus disease. The aim of the project is to use high throughput sequencing to characterise the host response in infection with both Plasmodium falciparum and Ebola virus compared to Ebola virus and Plasmodium falciparum only. The experimental plan is to use RNA sequencing to simultaneously quantify the amount of Ebola virus and Plasmodium in patients and perform differential gene expression to identify changes in the host response focusing on the innate immune response. These will then be investigated to identify parameters that are associated with outcome (survival/death/inflammatory response).

The project is a joint studentship between the University of Liverpool and the Singapore Immunology Network at A*STAR in Singapore. The project will be supervised by Prof. Julian Hiscox (Liverpool) who used sequencing to characterise Ebola virus infection (Carroll et al. 2014. Nature) and the host response (Liu et al. 2017. Genome Biology) and Prof. Laurent Renia (A*STAR) who focuses on Plasmodium (Gruszczyk et al. 2018 Science). In Year 1 the student would sequence human samples and use bioinformatics to identify and quantify the amount of Ebola virus and Plasmodium and also cellular genes that correlate with outcome and respond to infection. In Year 2, the student would move to A*STAR to examine the datasets with regard to factors specifically associated with Plasmodium infection and how these correlate with animal models. Moving into years 3 and 4 they would then use Ebola sub-viral assays in the presence of Plasmodium to investigate how deletion/over-expression of the identified genes influences virus biology and investigate how these responses maybe therapeutically manipulated to influence towards survival.

Julian A. Hiscox is Chair in Infection and Global Health at the University of Liverpool. His laboratory currently consists of 3 PDRAs and 8 PhD students. Two of the PDRAs will provide specific sequencing and informatics support to this PhD project. Julian has supervised 19 PhD students through to the successful completion of their PhDs. For the past six years the major focus of his research group has been on Ebola virus infection.

Laurent Renia is the Executive Director, Singapore Immunology Network, Biomedical Science Institute (BMSI), Agency for Science, Technology and Research (A*STAR). He has mentored or mentoring 13 post-doctoral fellows, 14 PhD students (6 ongoing), 34 undergrad (Master/honors/Final year project) students, 7 technicians and 37 attachment students. His major research is correlations of protection or pathology during parasite infection focusing on malaria and other pathogens.

Please submit your application direct to Professor Hiscox via email. The application must consist of a 1-page covering letter and a no more than 2-page CV and be a single combined pdf and attached to the email. Any document that is either longer than the 3 pages or not a pdf will not likely be considered.

Funding Notes

This is a jointly funded project that covers Home rate academic fees and a UK stipend for 2018/2019 entry of £14,777 per annum, for the proportion of the project based in the UK. While in Singapore, the stipend is $2500 (Singaporean) per month.

References

1. Carroll et al. 2017. Deep Sequencing of RNA from Blood and Oral Swab Samples Reveals the Presence of Nucleic Acid from a Number of Pathogens in Patients with Acute Ebola Virus Disease and Is Consistent with Bacterial Translocation across the Gut. mSphere. 2(4). pii: e00325-17. doi: 10.1128/mSphereDirect.00325-17.
2. Bosworth A, Dowall SD, Garcia-Dorival I, Rickett NY, Bruce CB, Matthews DA, Fang Y, Aljabr W, Kenny J, Nelson C, Laws TR, Williamson ED, Stewart JP, Carroll MW, Hewson R, Hiscox JA. 2017. A comparison of host gene expression signatures associated with infection in vitro by the Makona and Ecran (Mayinga) variants of Ebola virus. Sci Rep. 2017 7:43144. doi: 10.1038/srep43144.
3. Carroll MW, Matthews DA, Hiscox JA, et al. 2015. Temporal and spatial analysis of the 2014-2015 Ebola virus outbreak in West Africa. Nature. 524:97-101.
4. Gruszczyk J, Kanjee U, Chan LJ, Menant S, Malleret B, Lim NTY, Schmidt CQ, Mok YF, Lin KM, Pearson RD, Rangel G, Smith BJ, Call MJ, Weekes MP, Griffin MDW, Murphy JM, Abraham J, Sriprawat K, Menezes MJ, Ferreira MU, Russell B, Renia L, Duraisingh MT, Tham WH. 2018. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax. Science. 359(6371):48-55. doi: 10.1126/science.aan1078.
5. Teo TH, Howland SW, Claser C, Gun SY, Poh CM, Lee WW, Lum FM, Ng LF, Rénia L. 2018. Co-infection with Chikungunya virus alters trafficking of pathogenic CD8+ T cells into the brain and prevents Plasmodium-induced neuropathology. EMBO Mol Med. 10(1):121-138. doi: 10.15252/emmm.201707885.


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