Hepatitis E virus hijacks a human blood-clotting enzyme to replicate inside cells, making it unique among known viruses. The virus causes over 20 million infections each year worldwide, with mortality rates reaching 25% in pregnant women, yet no treatment or vaccine exists. Most related viruses produce their own enzyme to chop up a large polyprotein into functional pieces, but HEV appears to lack this enzyme entirely. Instead, it relies on the host protease thrombin—normally involved in blood clotting—to process its polyprotein and control replication. This project will determine exactly how thrombin regulates HEV replication. If the research succeeds, it could identify existing thrombin inhibitors already used in clinics as potential antiviral drugs against HEV. This would offer a rapid route to treatment for a neglected global pathogen that spreads through contaminated food and water and also jumps from pigs to humans. The work is fundamental virology, but it targets a concrete therapeutic opportunity: repurposing approved drugs against a virus that currently has none.
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Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide, for which there is no treatment or vaccine. Although generally HEV infection has a low mortality rate, in some situations (e.g., during pregnancy) this can reach 25%.The WHO estimates that there are >20 million cases of HEV infection p.a., resulting in >3% of all viral hepatitis-related mortalities. The virus is transmitted through consumption of contaminated food/water, however, it also infects animals (e.g., pigs) from which it can be transmitted to humans zoonotically. HEV was unrecognised until the 1980s and many fundamental aspects of the viral replication-cycle are not understood. Understanding how HEV replicates to cause disease can identify therapeutic targets. All viruses related to HEV produce a large polyprotein that is digested by a virally produced proteolytic enzyme to generate functional protein units and is essential for controlling virus replication. However, we are starting to understand that HEV breaks this dogma. Instead, we propose HEV does not produce a protease and is dependent on a host cell protease such as thrombin for replication, making HEV biologically unique. The aim of this proposal is to understand how thrombin acts as a key, novel, regulator of polyprotein processing to control HEV replication. Importantly, HEV replication is sensitive to clinically used thrombin inhibitors. A greater understanding of how the HEV polyprotein is processed and the function of host proteases would benefit global populations through the identification of novel therapeutic targets.
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