Dr Jamel Mankouri

Introduction

Newly identified factors leading virus entry, survival, and release, are cellular ion channels, proteins that act as a pore in the membranes of all cells within the body, permitting the selective passage of ions (such as potassium ions, sodium ions, and calcium ions). Through controlling ion passage, these channels serve many critically important cellular functions. Malfunction of ion channels leads to human disease.

We have recently shown that by pharmacologically modulating cellular ion channels, we can impede the lifecycles of an array of important human viruses, notable examples including Bunyaviruses, Human Respiratory Syncytial Virus, Merkel cell polyomavirus, BK polyomavirus, Hepatitis C virus and Chikungunya virus.

Research in my laboratory focuses on understanding why these viruses require ion channel activity. This will allow a better understanding of the host cell processes that viruses require in order to survive.

Current major projects

  • Ion channel modulators as anti-viral drugs
  • Direct effects of ions on virus structures
  • Identification of new virus-ion channel interactions

Detailed research programme

Ion channel modulators as anti-viral drugs

Our research aims to elucidate the mechanisms by which disease causing viruses persist in human hosts. Ultimately we wish to identify new targets for therapeutic intervention, focussing on cellular ion channels. As an example, we have recently shown that three different bunyaviruses (Bunyamwera virus, Schmallenberg virus and Hazara virus) require potassium (K+) channels to infect cells (Hover et al., 2016 JBC; Hover et al., 2018 PLoS Path; Charlton et al., 2019 JBC). Our work is identifying the exact ion channel(s) required by these viruses, and elucidating why these channels are so important to the bunyavirus infection cycle. As bunyaviruses need these channels to multiply, we may be able to treat potentially fatal bunyavirus disease through blocking the channels using drugs. This would be exciting as ion channels are an established therapeutic target, and their modulators are in widespread human use.

Direct effects of ions on virus structures

To cause disease, viruses must gain entry into cells, commonly achieved through the endocytic network. Enveloped viruses escape endosomes using specialised spike proteins that cover the virion exterior and promote fusion. To cause fusion, these spikes interact with specific chemicals within endosomes and dramatically change shape. The fusion spikes then interact with the endosomal membrane and force this membrane to mix with the viral envelope. When the membranes merge, fusion has occurred and the viral genome is released into the cytoplasm.

We have recently shown for the first time that bunyaviruses require K+ ions in endosomes to cause structural alterations in the spike proteins leading to fusion (Punch et al., 2018 JBC). We are now investigating whether the requirement for K+ is a general characteristic of other viruses within the broader bunyavirus group.

Identification of new virus-mediated channel alterations

The importance of cellular ion channels during virus infection is only now being recognised. We were amongst the first to reveal that viruses subvert host cell ion channel function to modify the cellular environment and favour viral growth at the expense of the host. To advance this field, we are open to collaborations to identify new virus-ion channel interactions. It is exciting to think that appropriate ion channel drugs for many viruses may already be in clinical use.