Professor Mark Harris

Profile

1983-1987 PhD at the Institute of Virology, Glasgow

1987-1988, Post-doctoral position with Dr Possee, NERC Institute of Virology, Oxford;

1988-1993 PostDoctoral Research Fellow, MRC Retrovirus Research Laboratory, Department of Veterinary Pathology, Glasgow;

1993-1998 MRC Senior Research Fellowship, MRC Retrovirus Laboratory, Glasgow, (moved to Department of Microbiology, University of Leeds in 1997).

Research interests

Virus-host interactions and mechanisms of virus replication

Hepatitis C virus

Hepatitis C virus (HCV) is an important human pathogen that infects an estimated 73 million people worldwide. My laboratory is interested in understanding the molecular mechanisms by which this virus replicates its genome and assembles into new virus particles, with a particular focus on the virus-host interactions that underpin these processes. Although new direct acting antivirals (DAAs) have revolutionised the treatment of HCV infection there is still a need to understand the details of virus biology. We are particularly interested in the functions of the HCV NS5A protein, a target for one class of DAAs whose mode of action remains unclear.

Specific projects include:

Role of NS5A in virus assembly and the involvement of PKR

NS5A has a key role in virus genome replication but in addition we recently demonstrated a novel role for NS5A in the process of assembly of infectious virus particles (Yin et al, 2018, Chen and Harris, 2022).  We recently showed that this role involves antagonising a previously uncharacterised function of the interferon-induced kinase PKR.  Ongoing studies will identify the molecular effectors of this function.  We will leverage our experience with other RNA viruses to evaluate if these effects are specific to HCV or pan-viral.

Studies on HCV genotype 3 NS5A

Nearly 50% of HCV infections in the UK are genotype 3 and this manifests in both higher levels of resistance to the DAAs and more severe disease pathology.  However, neither of these characteristics are understood.  We have started to use recently developed culture systems for genotype 3 HCV to study the role and functions of NS5A as it is likely that these differ significantly from other, more well studied, genotypes (1 and 2) (Kelly et al, 2017).   

Chikungunya virus

Chikungunya virus (CHIKV) is a mosquito-transmitted virus that has re-emerged over the past decade to cause large epidemics across the globe.  The virus causes fever, rash, arthritis and can sometimes be fatal.  The biology of CHIKV is poorly understood and our studies focus on one of the viral proteins, nsP3, which has a number of characteristics in common with HCV NS5A.  Ongoing projects are seeking to characterise the functions of each of the three domains of nsP3 by mutagenesis in the context of infectious CHIKV and analysis of virus replication in both human and mosquito cells – these studies have revealed intriguing host specific phenotypes.  We are also using a range of cutting-edge techniques such as proteomics, iCLIP and super-resolution microscopy to identify host cell proteins or RNAs that interact with nsP3 and characterise the effects of nsP3 on the morphology of infected cells.

We are also collaborating with researchers in Brazil to screen novel compounds derived from natural products for antiviral activity, particularly against CHIKV but also other important  viruse such as SARS-CoV-2.

Ebolavirus

Ebolavirus (EBOV), a member of the Filoviridae family, is a causative agent of a severe haemorrhagic fever in humans with a mortality rate of greater than 50%.  The recent outbreak of EBOV in West Africa resulted in the death of more than 11,000 individuals, as well as profoundly affecting the infrastructure, productivity and social fabric of affected countries.  Despite improvements in the containment and management of the disease, effective therapeutic options for the treatment of infected individuals are lacking, in part due to the need to propagate EBOV under Biological Safety Level (BSL) 4 containment.

In collaboration with Prof Colin Fishwick and Dr Martin McPhillie (School of Chemistry) we are using a combination of computer-aided molecular design coupled with synthetic chemistry and an EBOV mini-genome assay (which allows EBOV replication to be measured at BSL2), to design and validate small molecules targeted to a conserved hydrophobic pocket in the EBOV nucleocapsid protein (NP).  This pocket binds a peptide from the N-terminus of the VP35 cofactor, and this interaction is essential for EBOV gene expression and thus viral replication. Excitingly, this approach yielded a number of small molecules that selectively inhibited EBOV gene expression with nanomolar EC50 values.  Ongoing projects will further develop and optimise these compounds and also expand the approach to other targets in EBOV replication.

SARS-CoV-2 

Again in collaboration with Colin Fishwick and Martin McPhillie we are using a combination of computer-aided molecular design and virus/replicon assays to identify novel inhibitors of the SARS-CoV-2 nsp14 exoribonuclease (the proof-reading enzyme).  We are examining the ability of these to inhibit virus replication in combination with nucleoside analogues (eg remdesivir or molnupiravir). 

We are part of the Virology and Structural Molecular Biology groups

• Characterisation of a novel role for PKR in inhibiting virus assembly
• Live cell imaging capability for research on pathogenic viruses

Qualifications

• BSc, Plymouth, PhD 1987, Glasgow

Professional memberships

• Microbiology Society
• American Society for Virology

Student education

Undergraduate and taught Postgraduate project topics:

• Virus-host interactions in hepatitis C virus and chikungunya virus
• Replication of hepatitis C virus and chikungunya virus
• Development of inhibitors of Ebola virus replication

See also:

• Faculty Graduate School
• FindaPhD Project details:
  • Project 41270

Academic roles: Chair, Faculty of Biological Sciences Biological Safety Committee