This project is part of the DPhil in Biology at the University of Oxford
Viruses with RNA genomes like dengue, Zika, polio and vesicular stomatitis virus have the potential to evolve rapidly, over similar timescales to transmission, due to the lack of a proof-reading polymerase (e.g. reference 1). In addition to replication errors due to low fidelity, for some viruses, their intracellular replication strategy also increases mutation rates (2). There is therefore potential for selection to occur at both the within and between-cell levels. Although a large body of theoretical work has focussed on the evolutionary dynamics of phage at the between-cell level (3-7), fewer studies have focussed on the evolutionary dynamics of RNA viruses of protozoa and animals at these small scales. Advances in single-cell virology are enabling the study of within-cell dynamics of viruses (8,9), but models of within cell dynamics and, particularly, those linking within and between cell virus replication are scarce. Therefore, the impact of within-cell virus activities on between-cell transmission and multiscale evolutionary dynamics remains to be more thoroughly quantified.
Aims
This PhD project will focus on how intracellular replication dynamics of RNA viruses introduce trade-offs at the between-cell level and quantify the implications of trade-offs for virus fitness across these two scales.
Virions cannot be immediately released from infected cells; they must go through six steps before mature virions are produced. The strategy a virus takes through these steps influences the mutation rate, virus yield, the time to infection of new cells and potentially the cell death rate. All these factors influence between-cell transmission dynamics and trade-offs between them may influence virus evolutionary strategies. For example, an increase in replication rate may lead to earlier cell death. Viruses of protozoa and animals are capable of exiting cells either by keeping the host cell alive and budding from the cell membrane, or inducing apoptosis and releasing virions during cell death (summarised in (10). Using a mathematical model of between-cell transmission, we have recently shown that fitness minima exist at this level with respect to the time it takes for virus to kill the cell, when either virus can exit by budding or by killing the host cell (10). This means that intermediate times to apoptosis lead to virus fitness that is lower than short times to apoptosis; leading to an apoptotic strategy, and long times to apoptosis; leading to a budding strategy.
This PhD project will build on this work to investigate different drivers of virus transmission and virulence such as within-cell replication events. The project will draw on the rich approaches in mathematical biology to develop models to understand the dynamics of between-cell transmission. There is considerable scope for experiments to test resulting predictions and, in particular, to specialise on the evolutionary dynamics of mosquito-borne viruses.
This project is part of the Microbiology & Infectious Disease theme in the Department of Biology.
Funding
This project is part of the DPhil in Biology programme, and is not a funded course at the University of Oxford, as such, students are expected to explore options for funding. However, we anticipate being able to offer around 6 full graduate scholarships to incoming DPhil Students in 2023-24
You will be automatically considered for the majority of Oxford scholarships, if you fulfil the eligibility criteria and submit your graduate application by 20 January 2023. Scholarships are awarded on the basis of academic achievement and potential to excel as a DPhil student.
For further details about searching for funding as a graduate student visit the University’s dedicated Funding pages.
Eligibility
For full entry requirements and eligibility information, please see the main admissions page.
How to apply
The deadline for applications for 2023-2024 entry is midday 20 January 2023. We will continue to accept applications submitted after 20 January 2023, but these late applications will not be considered for scholarship funding.
You can find the admissions portal and further information about eligibility and the DPhil in Biology Programme at the University's graduate admissions page.