Molecular mechanisms of host restriction of arenaviruses and viral antagonism

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The Global Issue: Disease emergence from viruses that spill-over to humans from their natural animal reservoir host is difficult to predict. Influenced by several environmental, biological and lifestyle factors, emerging and re-emerging viral infections are occurring with increasing frequency in the 21st century, particularly in the absence of effective measures to prevent and control epidemics that have the potential to develop into virus pandemics. Endemic to West Africa and South America, arenaviral haemorrhagic fevers, such as Lassa fever (LF), are on the priority list of the World Health Organisation (WHO) as diseases requiring urgent research and development measures. Human transmission occurs through direct skin contact with infected rodent faeces or urine, ingestion of contaminated food, or through respiratory exposure to rodent excreta, resulting in illnesses ranging from mild flu-like syndromes to severe and highly fatal haemorrhagic diseases. Recent increased frequency of outbreaks in Nigeria of Lassa virus (LASV) has emphasised that these viruses should no longer be treated as causes of sporadic epidemics. The immense public health and socio-economic impact of these outbreaks in Nigeria and other endemic countries is further exacerbated by the lack of vaccines and effective treatments. Background: The interplay between host protective processes, i.e. cellular immunity, and viral replication is a key determinant of disease outcome during arenavirus infection; with potent suppression of the first line of defence mechanisms against invading pathogens being a hallmark of LASV infection. Host restriction factors are protein components of the intrinsic anti-viral response to infection. These proteins act at crucial steps to potently inhibit viral entry, replication and exit from the host cell. I have for the first time demonstrated a restriction of virus entry by the zinc metalloprotease, ZMPSTE24 and a novel synergistic inhibitory activity by ZMPSTE24 and another host restriction factor family - the interferon-induced transmembrane proteins (IFITMs). Virus entry is a key determinant of viral host range, of the ability to productively infect particular cell types, and of disease outcome, hence, targeting this step of the arenavirus lifecycle could have significant impact on the control of viral infection.Overarching aim: My research will address the existing knowledge gaps that hamper a deeper understanding of arenavirus interactions with human host cells and the urgent need to identify novel anti-viral therapeutic options. I will define the mechanisms of the ZMPSTE24 and IFITM host factors that inhibit arenavirus entry, unravel details of arenavirus infection dynamics that involve these host factors and determine the virus life cycle adaptations that allow escape from these host inhibition pressures. Key Objectives: 1) Determine the physical effects that ZMPSTE24 and IFITMs have on the structure of the cell's barriers to infection, i.e. membranes, that underpin the mechanism of ZMPSTE24 and IFITMs, 2) Explain the role of arenavirus proteins in overcoming ZMPSTE24-IFITM activity, and 3) Reveal how the antiviral mechanisms of ZMPSTE24 shape the arenavirus life cycle, thus opening up potential avenues for targeted therapeutic strategies.Altogether, this study will identify and characterise the processes that are modulated by arenaviruses, thus providing key information for the development of specific and effective antivirals, in the longer term. This research is underpinned by strong preliminary data and benefits from my expertise and strong collaborations with other arenavirus experts and biophysical chemists. I also collaborate with infectious disease epidemiologists in Nigeria, hence in the future, this proposal will aim to accelerate and integrate community-focused approaches to prevent future epidemics through public engagement in regions identified as vulnerable to arenavirus outbreaks.