Professor Mark Harris

Professor Mark Harris

Profile

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:

1)      Role of NS5A in virus assembly

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).  Ongoing studies will determine the molecular basis for this function, in particular identifying the cellular and viral proteins that interact with NS5A to mediate virus assembly.

2)      Phosphorylation of NS5A

NS5A is extensively phosphorylated, our recent studies have determined sites of phosphorylation and identified some of the functional consequences of this post-translational modification (eg see Goonawardane et al 2017, Ross-Thriepland et al 2015, 2014).  We are continuing these studies to identify the cellular kinases that phosphorylate NS5A and further analyse the downstream consequences for protein-protein interactions, sub-cellular localisation and roles of NS5A in both virus genome replication and assembly.

3)      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 arboviruses such as Dengue and ZIKA.

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 (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.

We are part of the Virology and Structural Molecular Biology groups

Research in my laboratory is funded by the Wellcome Trust and Medical Research Council, studentships are funded by the BBSRC, China Scholarship Council and University of Leeds.

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, Department of Microbiology, University of Leeds.

Research interests

Virus-host interactions in hepatitis C virus and Chikungunya virus.

<h4>Research projects</h4> <p>Any research projects I'm currently working on will be listed below. Our list of all <a href="https://biologicalsciences.leeds.ac.uk/dir/research-projects">research projects</a> allows you to view and search the full list of projects in the faculty.</p>

Qualifications

  • BSc, Plymouth, PhD 1987, Glasgow

Professional memberships

  • The Microbiology Society
  • American Society for Microbiology

Student education

Undergraduate 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:

Academic roles:

  • PGT Programme Leader sub-degrees - Infection, Immunity and Human Disease

Committees:

  • Member of Masters Taught Student Education Committee (Co-opted member)

Current postgraduate research students

<h4>Postgraduate research opportunities</h4> <p>We welcome enquiries from motivated and qualified applicants from all around the world who are interested in PhD study. Our <a href="https://biologicalsciences.leeds.ac.uk/research-opportunities">research opportunities</a> allow you to search for projects and scholarships.</p>