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Precision Medicine DTP - Inhibition of Zika Virus by Interferon A14 and derivatives


College of Medicine and Veterinary Medicine

About the Project

Background
Type I interferons can be produced by most cells in the body upon virus infection and are central to innate immune control and subsequent elimination of virus infection. There are twelve human interferon alpha (a type I interferon) subtypes. Yet only the IFNa2a subtype is used clinically for treatment against certain chronic hepatitis C virus infections together with ribavirin. Yet in prior experiments it has been shown that IFNa2a has only weak antiviral activity and that there are in in fact more potent IFNa subtypes. For example, IFNa14 has been shown to be highly active against viruses such as influenza A virus and HIV. In light of these data it is important to revaluate the therapeutic utility of type I interferon subtypes in the current context of a deficit of broad-spectrum antivirals and emerging viral disease, as highlighted by current attempts to use a type I interferon against the causative agent of COVID-19, SARS-CoV-2 in clinical trials. Working with our commercial partner ILC Therapeutics, we have access to novel hybrid IFNa’s as well as in-house synthetic and naturally occurring IFNa variants all based in the IFNa14 backbone.
Zika Virus is a mosquito borne flavivirus which can be transmitted vertically from mother to infant to cause a range of birth defects such as microcephaly and grouped under the name congenital Zika syndrome, as well as causing Guillain-Barré syndrome in some instances. Currently there are no therapeutics or licensed vaccine for Zika virus, though there is some evidence of control by IFNa2a. Thus understanding if IFNa14 or derivatives can exert augmented viral control could be of biomedical importance.
Aims
The overall aim of this study is test if IFNa14 and derivatives have antiviral activity against Zika virus infection. To do this we will:
1. Test different IFNa subtypes and synthetic IFNa derivatives for inhibition of Zika virus (using South American lineage virus) by plaque assays, reporter assays, and qPCRs.
2. To identify interferon stimulated genes (ISGs) via RNA-Seq analysis in cells stimulated with different IFNa subtypes and identify ISGs that are differentially expressed.
3. Validate the identified ISGs with qPCR and pulse SILAC proteomic analyses.
4. Generate ISG overexpression cell lines and knock-out cell lines to test for resistance and sensitivity to Zika virus.
5. Determine the role of Zika virus protein NS5 in counteracting affecting the antiviral activity of different IFNa subtypes.
Collectively, this project will employ datasets generated from RNA-Seq and broad spectrum proteomics in conjunction with quantitative analytical data on Zika virus infectivity to analyse whether IFNa14 and derivatives have enhanced antiviral activity against Zika virus infection. It will identify the principal ISGs that inhibit Zika virus infection and will determine the ability of Zika virus to counteract these.

Training outcomes
Full training will be given in a range of molecular, cellular, genomic and proteomic level techniques in the context of viral infection, cell biology and immunology, these include; eukaryotic cell culture, viral infection and plaque assays, CRISPR/Cas9 gene editing, western blot, confocal microscopy, PCR, qPCR, RNA-sequencing, and mass spectrometry. The student will acquire bioinformatics skills in the analysis of large data sets using, for example, MaxQuant (proteomic data) and CLC genomics workbench (RNA-Seq). Training in classical/molecular virology techniques will be provided. While the student will also learn how to produce and purify type I interferon via interaction and placement with ILC therapeutics, where they will also benefit from in depth expertise in many aspects of type I interferon and innate immunity.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2021

Qualifications criteria: Applicants applying for an MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area. The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,285 (UKRI rate 2020/21).

Full eligibility details are available: View Website

Enquiries regarding programme:

References

Infection with a Brazilian isolate of Zika virus generates RIG-I stimulatory RNA and the viral NS5 protein blocks type I IFN induction and signaling. Hertzog J, Dias Junior AG, Rigby RE, Donald CL, Mayer A, Sezgin E, Song C, Jin B, Hublitz P, Eggeling C, Kohl A, Rehwinkel J. Eur J Immunol. 2018 Jul;48(7):1120-1136. doi: 10.1002/eji.201847483.

Inhibition of type I interferon induction and signalling by mosquito-borne flaviviruses. Cumberworth SL, Clark JJ, Kohl A, Donald CL. Cell Microbiol. 2017 May;19(5). doi: 10.1111/cmi.12737.

Interferon-α Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms. Harper MS, Guo K, Gibbert K, Lee EJ, Dillon SM, Barrett BS, McCarter MD, Hasenkrug KJ, Dittmer U, Wilson CC, Santiago ML. PLoS Pathog. 2015 Nov 3;11(11):e1005254. doi: 10.1371/journal.ppat.1005254.

Harnessing the therapeutic potential of host antiviral restriction factors that target HIV. Sloan RD, Wainberg MA. Expert Rev Anti Infect Ther. 2013 Jan;11(1):1-4. doi: 10.1586/eri.12.146.

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