Congratulations to the nominees for the Ker Memorial Prize 2023

Supervisor:  Dr Jo Stevens (Roslin Institute)

About her work:  Mycobacterium avium ssp paratuberculosis (MAP) is the causative agent of Johne’s disease (JD), a chronic inflammatoru bowel disease of ruminants common world-wide.  There is no treatment for JD, and the current diagnostic tests are ineffective.  Rose investigated the initial interaction between MAP and the intestinal lining of infected animals.  She studied the role of a number of MAP surface proteins to obtain greater understanding of MAP pathogenesis, and identify better diagnostic and therapeutic targets. 

She went on to study several model bovine intestinal organoid systems to assess their ability to model a MAP infection in a physiologically representative system, highlighting the need for multicellular models which accurately represent the pathogen target cell type/s in vivo.

Supervisor:  Prof Andrew Leigh-Brown (School of Biological Sciences)

About her work:  Heather’s PhD work described HIV evolution in Uganda using full-genome data spanning from 1986 to 2016.  In a modern dataset, the HIV envelope gene was found to be a ‘cold-spot’ for recombination. This envelope region is almost always found intact likely because the translated protein undergoes intricate folding, disruption of which renders the virus unable to infect new cells.

Historical samples from 1986 rediscovered in storage were sequenced with new techniques to obtain 109 genomes. This showed a shift in subtype composition and phylodynamic analysis revealed many lineages are no longer found.  A remarkably high predicted co-receptor CXCR4 usage suggested infections in the early epidemic progressed faster to AIDS. These early viruses would thus have had reduced fitness during a time when AIDS education limited infection opportunities. 

These findings characterise a highly diverse and complex epidemic in Uganda that has shifted over time, whilst recombination acted to generate a wide variety of unique recombinant forms. 

Supervisor:  Prof Andrew Rambaut (School of Biological Sciences)

About her work:  Viruses mutate as they replicate and spread. When a virus genome is sequenced, we can compare it to other genomes and make a family tree of these viruses, known as a phylogeny. At the same time, we can use information about where and when the viruses were sampled, combined with mutations, to explore how viruses spread in space and time. This is a part of the field of phylodynamics.

In my thesis, I explored how two important viruses, Ebola virus and SARS-CoV-2, have spread on small and large scales by applying phylodynamic methods to extensive genome sequence databases. I made a large-scale simulator of Ebola virus in Sierra Leone, to replay the tape of the epidemic to explore what could have happened under different conditions. I also studied the evolution of SARS-CoV-2 variants of concern, in particular how Alpha variant evolved; and then I investigated trends in the spread of different major COVID-19 waves across the UK, including how the impact of public health restrictions.

Using methods and analyses such as these while epidemics are ongoing can help provide another source of information on which to base public health decisions, and examine the effect of different interventions on the spread and evolution of viruses.

Supervisor:  Dr Sara Macias (School of Biological Sciences)

About her work:  Micro (mi)RNAs are short single stranded RNAs that prevent the building of proteins by binding to long RNAs, thereby regulating gene expression. During my PhD I studied the role of protein DGCR8, that is involved in the synthesis of miRNAs, but is also one of the proteins mutated in the developmental disorder 22q11.2 deletion syndrome. We found that (partial) absence of DGCR8 resulted in better antiviral immunity in stem cells but that stem cells could not mature into specific cell types anymore, indicting the need for further research into DGCR8 and its role in 22q11.2 deletion syndrome.

Supervisor:  Prof Amy Buck (School of Biological Sciences)

About her work:  Intestinal worms infect approximately a quarter of the world’s population as well as domestic and wild animals. They can establish chronic infections and their success as parasites relies on the release of various molecules that possess the ability to modulate the immune system of the host. During my PhD, I studied the gastrointestinal worm Heligmosomoides bakeri which infects mice to model how worm parasites can establish infections and to test new ways to treat or control gastrointestinal worms infections relevant to humans and animals.

As with other parasitic worms, H. bakeri releases proteins and RNA molecules, some of which are exported in packages known as vesicles. H. bakeri vesicles can be transferred to host cells and contain small RNAs and an Argonaute protein, termed “exWAGO”. As Argonaute proteins associate with small RNAs to regulate gene expression and hence protein production, we predict that exWAGO and the small RNAs released by the parasite can manipulate the expression of genes inside the host.

My PhD work presents a first insight into the mechanism of function of exWAGO in terms of what small RNAs and what proteins it interacts with. Whilst the quest of understanding how exWAGO operates inside host cells continues, my work shows that exWAGO can be a vaccine candidate for the intervention of gastrointestinal worm infections.

Supervisors:  Prof Ross Fitzgerald (Roslin Institute) and Prof David Dockrell (Centre for Inflammation Research)

About his work: My work aimed to identify macrophage responses to investigate as targets for host directed therapy against Streptococcus pneumoniae.

I applied a combined approach of: (1) looking for macrophage immune responses that unusually severe S. pneumoniae variants have evolved to resist; and (2) systematically identifying and integrating results from existing studies to prioritise genes to study in macrophages.

This approach identified roles for several genes in macrophage defence against S. pneumoniae that were also relevant to other medically-important streptococci. For two genes, drug compounds targeting the gene products increased bacterial killing by human and mouse macrophages. Overall, this work identified new mechanisms of macrophage host defence and potential targets for host-directed therapies.