Hughes Lab

Major outbreaks of childhood infections by pathogens such as the mumps and measles viruses continue to cause significant illness in young children despite the availability of effective vaccines. Additionally, infections with viruses for which there is no vaccine – such as parainfluenza viruses – lead to significant numbers of children needing intensive care treatment in hospital. These viruses belong to a highly related group that, in addition to being clinically relevant pathogens, serve as exceptional models in the laboratory for studying how our bodies respond to viral infections – knowledge that has the potential to be translated into effective treatments.

During our first-line defence against virus infection our cells produce factors (including proteins like interferon) aimed at combating the infection. This response, known as the innate immune response, involves the expression of hundreds of genes and places significant stress on our bodies. The products of these genes work in concert to directly target the infection, to trigger the arm of the immune response that involves antibodies and T cells and to regulate the magnitude of the innate response; the latter is essential as an uncontrolled response can lead to autoinflammatory diseases.
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Our research aims to understand how the innate immune response is controlled and how can viruses overcome our defences – knowledge that could be used to develop more effective antiviral therapies.

Technical summary:
In recent years, our work has focussed on understanding the interplay between virus infections and the ubiquitin-like (UbL) protein system, utilising DNA viruses (herpesviruses) and RNA viruses (particularly paramyxo- and pneumoviruses) as models. The attachment of UbL proteins to substrates represents one of the most vital posttranslational modifications in the cell and several UbLs have been identified including ubiquitin, NEDD8, SUMO and the interferon-inducible protein ISG15.

​Using a multidisciplinary approach, including molecular biology, cell biology & proteomics , the objective of our research is to gain a deeper understanding of virus-host interactions. In doing so, we may also uncover novel therapeutic targets; the primary rationale for studying drugable cellular processes that hinder virus biology is the potential to identify therapies that viruses find harder to develop resistance to.

We recently demonstrated that for the oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), NEDDylation is critical for the maintenance of latency and reactivation of virus replication, both of which are required for the pathogenesis Kaposi’s sarcoma. Furthermore, in one of the first studies to demonstrate the potential of targeting this pathway for the treatment of virally-induced malignancy, we uncovered the molecular mechanisms that underpin cytotoxicity due to the inhibition of the NEDDylation pathway (Hughes et al. 2015., PLoS Path).

More recently, the molecular mechanisms that govern ISG15’s antiviral activity, in addition to its importance as a regulator of the antiviral response, has emerged. Our TENOVUS_Scotland-funded work has recently uncovered an exciting new mechanism that inhibits paramyxovirus transcription and replication. In addition, our Academy of Medical Sciences-funded research has begun to dissect the ISG15-dependent mechanisms that are essential for regulated interferon signalling, including identifying previously unknown functions of ISG15.

We have also developed novel tools, currently being marketed by Avacta Life Sciences, which can be used to dissect UbL-associated pathways at the cellular level (Hughes et al., 2017. Science Signaling; Tang et al. 2017, Science Signaling). We are always looking for new ways that we can use our knowledge of UbLs to tell us something about how our cells function. We are currently funded by TENOVUS-Scotland to develop new genome-wide CRISPR/Cas9 screens for improving the identification of virus restriction factors and pathways based on our genetically engineered ISG15.KO cell lines (described in Holthaus et al. 2020) – see our latest review.