Dr Morgan Herod

Introduction

The Herod lab has a broad interest in virus replication and host-cell interactions, with a particular interest in studying single-stranded positive-sense RNA viruses important for human and animal health. Our overarching aim is to use a deeper understanding of the molecular mechanisms of viral replication to develop new approaches to disease control.

The lab studies a range of viruses, with a particular interest in hepatitis E virus , foot-and-mouth disease virus and norovirus using a wide range of molecular virology approaches. Hepatitis E virus is a leading cause of acute viral hepatitis worldwide with a diverse host-range. Although hepatitis E virus infections are increasing, many molecular aspects surrounding infectivity are poorly characterised and novel zoonotic events are of global concern. Foot-and-mouth disease virus is a pathogen of cloven-hoofed livestock with a significant financial burden across the globe. Noroviruses collectively cause gastroenteritis, and are responsible for greater than 200,000 deaths, costing approximately ~£40 billion worldwide each year.

Current major projects

• How do viral capsids disassemble and enter the cell?
• How does viral polyprotein processing control replication?
• Which molecular interactions control virus genome replication?
• How are new virions assembled?

Detailed research programme

How does the norovirus capsid interact with cells and molecules to disassemble and regulate entry into the cell?

Norovirus particles consist of a genome enclosed within a protein shell or capsid. These capsids are important for protecting the genome for transfer between hosts. We use a broad range of techniques spanning molecular and structural biology, classical virology and genetics to understand the importance of the norovirus capsid during the early part of the virus life-cycle. This includes how the capsids interact with ligands and biomolecules, the conformational changes that can occur to capsids and how these factors control endocytosis, virion structure and infectivity. These are all essential viral processes that are required for the release of the genome to initiate an infection.

Which molecular interactions control viral genome replication and assembly of new virions?

Positive-sense RNA viruses synthesise new viral genomes in virally produced organelles sometimes referred to as “replication complexes”. These complexes are assembled from viral non-structural proteins that are produced via polyproteins. Processing of these polyproteins is key for controlling viral replication temporally and spatially. We use molecular virology approaches to reveal how these viral polyproteins are processed to generate functional non-structural proteins as a cornerstone for controlling viral RNA replication.

What host-virus protein interactions are important for replication and virion assembly?

Many types of positive-sense RNA viruses are thought to hijack cellular components including proteins and lipids to help build their “replication complexes”. However, for viruses such as norovirus, hepatitis E virus and foot-and-mouth disease virus, the host factors required for building viral “replication complexes” and for synthesis of new viral RNAs remain unknown. In the latter part of the viral life-cycle new virus particles are assembled from these newly synthesised genomes together with viral capsid proteins. This is believed to be a process that is tightly co-ordinated with genome synthesis but requiring different molecular interactions. Understanding which host proteins and interactions that are required for viral genome synthesis and virion assembly may provide a foundation for the development of antiviral therapies. Using structural, proteomics, molecular and cell-based techniques together with cell culture and replicon systems we are dissecting the composition of viral “replication complexes”, the interactions require for virion assembly, and the host protein and pathways required in these processes.

What is the molecular basis for viral zoonosis?

HEV is a zoonotic disease capable of spreading from animals, especially pigs, to humans raising the risk of future human spillover events. It has previously been suggested that specific protein sequences help the virus to adapt for a range of hosts. Using chimeric virus sequences between zoonotic and non-zoonotic viruses, we are investigating how the viral genome sequence affects viral replication efficiency and host range.