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Investigating nairovirus - host cell interactions using reverse genetics


Faculty of Biological Sciences

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Dr J N Barr Applications accepted all year round Funded PhD Project (UK Students Only)

About the Project

This project focuses on the molecular and cellular virology of nairoviruses, which are segmented negative sense RNA viruses classified within the broad Bunyavirales order. The nairovirus group contains many serious pathogens of human and animals such as Crimean-Congo hemorrhagic fever virus (CCHFV) and Nairobi sheep disease virus. CCHFV is of great interest due to its association with devastating hemorrhagic fevers in humans, which can carry case/fatality rates of up to 80%. Nairoviruses are arboviruses, infecting ticks, which can subsequently transmit the virus to mammalian hosts via a bite, and there is growing concern that climate change may expand the habitat range of the tick vector, leading to an increase in the burden of nairovirus-mediated human disease. 

The current project focuses on CCHFV and another nairovirus called Hazara virus (HAZV), which is a close relative of CCHFV, classified within the same CCHFV-serogroup. The project aims to identify critical host-pathogen interactions that are critical for nairovirus entry and also the formation of so-called ‘virus factories’ where many viral processes including gene expression and virion assembly take place. To do this work we will exploit our newly developed and versatile reverse genetics system for HAZV, which allows directed alteration of any genetic element within the HAZV genome. We have recently used this system to uncover critical interactions between HAZV and cellular vesicular transport networks, as well as understand how nairoviruses control their gene expression. 

The research plan will use genetically-engineered versions of HAZV that express fluorescent marker proteins, allowing the detection of HAZV processes in cells by direct visualization. Involvement of host cell factors will be determined using various host gene expression ablation techniques, with influence on virus entry, virus gene expression and virion assembly measured by tracking viral proteins, viral RNA and intact virions using state-of-the-art light and electron microscopy techniques. Findings with HAZV will be validated using other members of the nairovirus group, including CCHFV. 

Applicant profile:

Talented and motivated students passionate about doing virology research are invited to apply. Applicants should hold a first or upper second-class degree or equivalent in a relevant subject along with appropriate research experience and/or a Masters degree. The successful applicant be registered with The University of Leeds graduate school, with the work carried out at both Porton Down (PHE) and University of Leeds sites, within the Barr (Leeds) and Hewson (Porton) groups.


Funding Notes

This studentship is open to home students only. Successful applicants will be awarded a non-taxable annual stipend at the rate of £17,609 per annum for 42 months, starting late September 2021. Annual increases to match MRC London rates will be applied for the duration of the project. All registration fees are included.

References

1. Rescue of Infectious Recombinant Hazara Nairovirus from cDNA Reveals the Nucleocapsid Protein DQVD Caspase Cleavage Motif Performs an Essential Role other than Cleavage.
Fuller J, Surtees RA, Slack GS, Mankouri J, Hewson R, Barr JN.
J Virol. 2019 Jul 17;93(15):e00616-19. doi: 10.1128/JVI.00616-19. Print 2019 Aug 1.
2. Hazara Nairovirus Requires COPI Components in both Arf1-Dependent and Arf1-Independent Stages of Its Replication Cycle.
Fuller J, Álvarez-Rodríguez B, Todd EJAA, Mankouri J, Hewson R, Barr JN.
J Virol. 2020 Aug 17;94(17):e00766-20. doi: 10.1128/JVI.00766-20. Print 2020 Aug 17.
3. Mutagenic Analysis of Hazara Nairovirus Nontranslated Regions during Single- and Multistep Growth Identifies both Attenuating and Functionally Critical Sequences for Virus Replication
Mega DF, Fuller J, Álvarez-Rodríguez B, Mankouri J, Hewson R, Barr JN.
J Virol. 2020 Aug 17;94(17):e00357-20. doi: 10.1128/JVI.00357-20. Print 2020 Aug 17.


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