Discovering new host-pathogen interactions to develop antivirals and vaccine strategies against PRRSV

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Porcine Reproductive and Respiratory Syndrome (PRRS) is a viral disease of pigs leading to major economic losses. The causative agent of the disease is PRRS virus (PRRSV), a rapidly evolving, small, enveloped positive-sense RNA virus. Modified live vaccines often prove ineffective in cross-protection and some have been shown to cause spreading infections. Thus, PRRS still has major impacts on animal health and welfare, resulting in reduction or loss of pregnancies, death in young piglets, and decreased growth rates in all PRRSV infected pigs. PRRSV is a master modulator of the host immune response. The virus infects cells of the innate immune response, specifically certain subsets of macrophages and dendritic cells. Upon PRRSV infection cytokine secretion and the innate host cell response are actively downregulated by the viral infection resulting in modulation of both the innate and adaptive immune response. The type I interferon (IFN) response is actively interfered with by multiple non-structural and structural proteins and is far from being fully understood (1). The interference of PRRSV with the immune system has impacts beyond PRRSV infection itself. Co-infections with other pathogens are enhanced due to the lack of immune response. Therefore, it is important to understand how PRRSV interferes with the host immune system and to identify viral factors involved in this process. This will give us tools to rationally attenuate PRRSV to generate more effective and safer vaccines.Viruses are mandatory intracellular parasites and use the cellular machinery to invade and manipulate the host to replicate the virions. Therefore, understanding the virus-host interaction is crucial to devising antiviral strategies, such as antiviral drugs, vaccines, genetic selection, or genome editing targets. FDA-approved drugs all target cellular pathways and are therefore an ideal starting point to use on primary macrophage cells to identify host machinery exploited by PRRSV during infection. Not only will the drugs identified as being antiviral allow further investigation into the host-pathogen interaction but the drugs and similar compounds may be developed for use in antiviral treatment.In this project we aim to identify viral genes involved in the downregulation of the IFN response and devise rational attenuation strategies for vaccines. We will also investigate the role of known antiviral genes of the interferon-inducible guanylate-binding protein (GBP) family, polymorphisms in which recently were shown to play a role in resilience towards PRRSV infection (2). Host-pathogen interaction mechanisms in primary alveolar macrophage cells will be investigated by performing an FDA-approved drug screen in collaboration with the lab of Dr Jason Mercer (MRC LMCB, London) and identified compounds followed up to identify their role in the viral replication cycle. This 4-year CASE studentship will provide excellent training in a variety of fields of biology, covering aspects of genomics and genetics, systems biology, virology, cell biology, innate immunology, biochemistry, and molecular biology. The successful candidate will learn and apply a wide variety of techniques, e.g. virological techniques (titration, purification), cell culture of primary cells and immortalized cell lines, fluorescence-activated cell sorting, western blotting, fluorescence microscopy, and many more. References1. Sun Y, Han M, Kim C, Calvert JG, Yoo D. 2012. Interplay between interferon-mediated innate immunity and porcine reproductive and respiratory syndrome virus. Viruses 4:424-446.2. Dekkers J, Rowland RRR, Lunney JK, Plastow G. 2017. Host genetics of response to porcine reproductive and respiratory syndrome in nursery pigs. Veterinary microbiology 209:107-113.