Title: Elucidating the molecular mechanism of hepatitis A virus initiation of infection
Funder: Medical Research Foundation

Abstract: In the years since 2013 Hepatitis A virus (HAV) has become a much more complex disease than previously thought. In 2013 my collaborator Prof Stanley Lemon (University of North Carolina, USA) showed that HAV, previously considered a non-enveloped virus, in fact exists both in a “naked” and in an “enveloped” form, both forms are infectious and play a role in disease. Not only this has novel virological and immunologicalimplications, but also requires reassessing the results of early HAV studies. During 2016-2017, HAV has been emerging as a sexually transmitted disease. Changes in sexual practises are supporting outbreaks of this pathogen transmitted by the faecal-oral route. As in the case of HIV-1 and sexually transmitted diseases of bacterial aetiology, crucial population pockets could act as sentinel groups for future and larger scenarios. HAV is an ancient human pathogen, but hides a paradox that threatens the rich and developed regions of the modern world. Improved sanitation results in large sections of the adult population that not only are susceptible to HAV, but are also vulnerable to the most severe form of the infection. Therefore, paradoxically, the disease burden of HAV is higher in the developed world than it is in developing regions. Vaccines are available, but are expensive and difficult to produce, and therefore are not included in largescalevaccination strategies. Overall, it has become clear that a solid and refreshed effort is needed to understand HAV and reduce its threat and disease burden. My research proposal aims to elucidate the mechanism whereby HAV initiates infection and to lay the foundations for the development of anti-viral strategies that block infection. It focusses on the very poorly understood mechanism that RNA viruses use to deliver their genomic RNA to the host-cell cytoplasm to initiate infection. In a recent study, Groppelli et al., 2017,PLoS Path, I have tackledthe longstanding assumption that non-enveloped viruses, after entry via receptor-mediated endocytosis, gain access to the cytoplasm by bursting the endosome. I have shown that the picornavirus poliovirus uses a coordinated process involving viral and cellular components to generate an “umbilicus” that delivers the RNA across the intact endosomal membrane. My study is the first to elucidate this step in RNA viruses. I amnow in the unique position to assess crucial similarities and differences within distinct members of the virus family. I will use a combination of molecular and state-of-the-art structural biology approaches to investigate HAV RNA delivery in vitro and in cells, focusing on triggers for RNA extrusion and the organisation of RNA within the capsid. I will focus on both naked and “enveloped” HAV to tackle all the viral forms that are relevant to the disease. Capitalising on my expertise in viral entry, intracellular trafficking and uncoating, I am determined to establish and lead novel HAV research at the University of Leeds. Successful outcomes are ensured by anextremely strong network of collaborators and co-applicants.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION