Viruses pose major health threats to the UK and worldwide. This proposal will be key to understanding how humans respond to Ebola virus infection and elucidate the root causes of why some people live and some people die. During Ebola virus infection most individuals go on to develop an acute febrile illness (Ebola virus disease). They progress either down a fatal pathway with death as the outcome or go on to survive infection. Other infected individuals have sub-symptomatic infection where they display no or only mild signs of Ebola virus disease.
The hypothesis being tested is that there are key differences in patients with Ebola virus disease that leads to different outcomes: acute infection-survive, acute infection-fatal and sub-symptomatic-survive. There are three main Objectives that will test this hypothesis and deliver scientific excellence and state of the art training to the PhD student. The first Objective will delineate the host response in patients with Ebola virus disease to identify and map in fine detail underlying changes in host gene expression that differentiate the three outcomes; acute infection-survive, acute infection-fatal and sub-symptomatic infection-survive. In Objective Two the sequence data (both RNAseq and MinION) will be integrated using bioinformatic based approaches to identify similarities and differences in molecules and signalling pathways between the three categories of patients. The bioinformatic predictions in terms of activated or inhibited signalling cascades will be tested on independent samples using qRT-PCR analysis. The first two Objectives are very much building up the most detailed picture of the host response to Ebola virus infection and through informatics analysis will identify potential signalling pathways that are effect by infection and may also be involved in the host response and outcome. Objective Three will test whether activation/inhibition of selected pathways during virus infection influences disease severity using viral load and the effect on the viability of a host cell as a model system. The work will also validate whether the pathways are actually altered during virus infection.
The project will be based mainly at Public Health England (Porton Down) with short research and training visits to the University of Liverpool. The project will be co-supersized by Profs. Carrol and Hiscox who have worked extensively together.
Miles Carroll is currently Head of Research within the National Infections service of PHE. He has ~100 publications, 4 in Nature during the last 5 years, and is the PI or Co-PI on several EBOV related grants which amount to ~£4M over the last 5 years. Miles has successfully supervised 3 PhD students in collaboration with Prof Hiscox over the last 5 years. He is currently the primary supervisor of 1 second year PhD student and co-supervisor of 3 others. His research group at PHE Porton includes two PDRAs and 1 PhD student who are all studying aspects of EVD and natural acquired immunity.
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.
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.
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.
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.
Liu X, Speranza E, Muñoz-Fontela C, Haldenby S, Rickett NY, Garcia-Dorival I, Fang Y, Hall Y, Zekeng EG, Lüdtke A, Xia D, Kerber R, Krumkamp R, Duraffour S, Sissoko D, Kenny J, Rockliffe N, Williamson ED, Laws TR, N'Faly M, Matthews DA, Günther S, Cossins AR, Sprecher A, Connor JH, Carroll MW, Hiscox JA. 2017. Transcriptomic signatures differentiate survival from fatal outcomes in humans infected with Ebola virus. Genome Biology. 18(1):4. doi: 10.1186/s13059-016-1137-3.
Quick, J, Loman, N et al. 2016. Real-time, portable genome sequencing for Ebola surveillance. Nature. 11;530(7589):228-232.
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.