... understanding life in molecular detail

Dr Jamel Mankouri

Virus pathogenesis, Ion Channels, Cell Biology.


Newly identified factors shown to be important in 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 including chemical signaling, the regulation of pH, and the regulation of cell volume. Malfunction of ion channels can cause diseases in many tissues.

We have recently demonstrated that by pharmacologically modulating cellular ion channels, we can impede the lifecycles of an array of important human viruses. Research in my laboratory focuses on understanding why viruses require this ion channel activity. These studies will allow a better understanding of the host cell processes that viruses require in order to survive.

Current major projects include:
  • Identification of new virus-mediated channel alterations
  • Effects of ion channel drugs on viruses
  • Investigating why viruses mediate ion channel alterations
  • Visualizing channel and viral protein trafficking in living cells

Virus-ion channel interactions

Our research aims to elucidate the mechanisms by which disease causing negative sense RNA viruses persist in human hosts. Ultimately we wish to identify new targets for therapeutic intervention focussing on cellular ion channels as an emerging druggable virus-host interaction.

  1. Bunyaviruses

These are a group of over 350 different viruses spread throughout the globe. They are predominantly transmitted to humans by insects and are capable of causing fatal disease in humans, often as a result of devastating hemorrhagic fevers. Bunyaviruses are a serious and worrying threat to human health because they have enormous capacity to mutate and evolve into new strains. In addition, the fact that bunyaviruses are mostly spread by biting insects that are highly mobile means they can rapidly move into new geographic locations, causing widespread disease. Despite this huge threat, no preventative or therapeutic measures currently exist for any bunyavirus-mediated disease.

We have recently shown that three different bunyaviruses (Bunyamwera virus, Schmallenberg virus and Hazara virus) require ion channels in order to multiply within infected cells (Hover et al., 2016 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 ion channels in order to multiply, we believe that we may be able to treat potentially fatal bunyavirus disease through blocking the channels using drugs. Ion channel blocking drugs are an established therapeutic target, and are in widespread human usage for common diseases such as diabetes, anxiety and hypertension. Therefore, by identifying and characterizing the specific ion channel(s) required for bunyavirus infection, we may open up a new and exciting class of anti-viral targets for the design of either newly developed drugs, or even for repurposing existing treatments, to treat bunyavirus mediated disease.

  1. Human Respiratory Syncytial Virus

Human Respiratory Syncytial Virus (HRSV) is the main viral cause of lower respiratory tract (LRT) infection worldwide. Each year, HRSV causes 34 million LRT infections with 10% requiring hospitalization, with up to 199,000 deaths. There is no HRSV vaccine and current treatments are expensive and only moderately effective. A strong need for new anti-HRSV therapies exists.

We have identified that HRSV targets ion channels expressed in the respiratory epithelium in order to multiply. We are investigating how HRSV is able to manipulate the activity of these channels and why this benefits the virus lifecycle. We are additionally investigating several new virus-host cell interactions we have identified and effects of manipulating these interactions on the virus lifecycle.

  1. Rabies virus

Rabies virus (RABV) is a single-stranded negative sense RNA virus of the genus Lyssavirus that causes 40,000-70,000 reported deaths annually. The number of actual deaths is estimated as up to 100 times higher since only 2-3% of human cases are thought to be reported. As 40% of RABV infected individuals are children, the years of life lost due to RABV makes it the seventh most important global infectious disease. The majority of RABV disease occurs in developing countries and remains endemic in some regions. In Africa, a person dies of rabies every 20 minutes. Rabies has been classed as a NIAID category C priority pathogen, indicating it as an emerging infectious disease with the potential for mass human harm.

A wide array of RABV variants exist, ranging from highly pathogenic strains to attenuated RABV vaccine strains. Our RABV research investigates the host cell factors utilised by RABV during infection. We are further studying the impact of these interactions on the virus lifecycle and whether this differs between pathogenic and non-pathogenic strains of RABV. Additionally, we wish to develop compounds that will inhibit these virus-host interactions that could act as potential novel anti-viral drugs.

Detailed research programme                  Close ▲
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Royal Society University Research Fellow/UAF in SMCB
BSc Pharmacology, PhD 2006 Leeds

Post-doctoral Researcher (2006 - 2009)
Post-doctoral Researcher (2009 - 2011)
Royal Society University Research Fellow (2011-present)
University Academic Research Fellow (2016-present)

8.55a Garstang
School of Molecular and Cellular Biology
0113 343 5646
J.mankouri@leeds.ac.uk

http://www.fbs.leeds.ac.uk/staff/profile.php?tag=Mankouri_J

Selected Publications

  1. Mankouri J, Tedbury PR, Gretton S, Hughes ME, Griffin SD, Dallas ML, Green KA, Hardie DG, Peers C, Harris M. Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2010 107:11549-54.

  2. Hover S, King B, Hall B, Loundras EA, Taqi H, Daly J, Dallas M, Peers C, Schnettler E, Mckimmie C, Kohl A, Barr JN, Mankouri J Modulation of potassium channels inhibits bunyavirus infection Journal of Biological Chemistry291 3411-3422, 2016 DOI:10.1074/jbc.M115.692673

  3. Mankouri J, Dallas ML, Hughes ME, Griffin SD, Macdonald A, Peers C, Harris M. Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence.Proc Natl Acad Sci U S A. 2009 15:15903-8.

  4. Igloi Z, Mohl BP, Lippiat JD, Harris M, Mankouri J Requirement for chloride channel function during the hepatitis C virus life cycle Journal of Virology 89 4023-4029, 2015 DOI:10.1128/JVI.02946-14