Studentship: Defining the arthropod SUMOylation system and its functional role during arbovirus infection

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

IAH Studentship:There are over 100 medically important arboviruses such as yellow fever, dengue and Chickungunya. Often they cause only mild flu-like symptoms and are limited, in part, by the cell’s interferon response but, when able to subverts this response, the virus can spread to target organs leading to more sever outcomes.This ability to both subvert the host cell’s machinery and promote a favourable intracellular environment is doubly complex for arboviruses as they encode only a few proteins with which to effect it and must do so in two distinct cell types; mammalian and arthropod.In mammalian cells, arbovirus induce cellular responses that results in virus clearance and cell survival or virus replication and cell death while in arthropod cells they establish an equilibrium that promotes a persistent state of infection necessary for continued virus transmission.Clearly, identifying mechanisms by which arboviruses affect their environment is fundamental to understanding the infectious process and host response.One mechanism recently shown to influence both is protein SUMOylation. SUMOylation is a dynamic modification that alters a proteins function and/or sub-cellular localisation. The recently identified response of SUMO to virus infection has significantly contributed to our understanding of viral pathogenesis in mammalian cells. Little is known, however, about SUMO and arboviruses and nothing about SUMOylation in the arthropod cell.This project will investigate the roll of SUMOylation in modulating arbovirus infection of mammalian and arthropod cell. The student will first establish cellular systems with a disrupted SUMO profile in which the phenotype of virus growth is altered.This will provide the basis for their research into understanding how mechanisms of SUMOylation in arbovirus infection of both mammalian and arthropod cells. In addition the student will produce, for the first time, data that described the SUMOylation machinery in arthropod cells.

Publications

10 25 50
 
Description Mosquitoes are responsible for the transmission of many clinically important arboviruses that cause significant levels of annual mortality and socioeconomic health burden worldwide. Deciphering the mechanisms by which mosquitoes modulate arbovirus infection is crucial to understand how viral-host interactions promote vector transmission and human disease. SUMOylation is a post-translational modification that leads to the covalent attachment of the Small Ubiquitin-like MOdifier (SUMO) protein to host factors, which in turn can modulate their stability, interaction networks, sub-cellular localisation, and biochemical function. While the SUMOylation pathway is known to play a key role in the regulation of host immune defences to virus infection in humans, the importance of this pathway during arbovirus infection in mosquito vectors, such as Aedes aegypti (Ae. aegypti), remains unknown. Significant biochemical differences were demonstrated between Ae. aegypti and Homo sapiens SUMOylation pathways and identify cell-type specific patterns of SUMO expression in Ae. aegypti tissues known to support arbovirus replication. Importantly, depletion of core SUMOylation effector proteins (SUMO, Ubc9 and PIAS) in Ae. aegypti cells led to enhanced levels of arbovirus replication from three different families; Zika (Flaviviridae), Semliki Forest (Togaviridae), and Bunyamwera (Bunyaviridae) viruses. Our findings identify an important role for mosquito SUMOylation in the cellular restriction of arboviruses that may directly influence vector competence and transmission of clinically important arboviruses.
Exploitation Route Further research into the role of SUMOylation in the replication and transmission of important arthropod transmitted pathogens.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology