{"id":93,"date":"2022-01-18T01:47:43","date_gmt":"2022-01-18T01:47:43","guid":{"rendered":"https:\/\/biology.st-andrews.ac.uk\/research\/?post_type=research_theme&p=93"},"modified":"2022-02-25T14:07:17","modified_gmt":"2022-02-25T14:07:17","slug":"infection-and-immunity","status":"publish","type":"research_theme","link":"https:\/\/biology.st-andrews.ac.uk\/research\/research-theme\/infection-and-immunity\/","title":{"rendered":"Infection and immunity"},"content":{"rendered":"

BSRC infection biologists\u2019 study basic and applied aspects of viral, bacterial and parasite pathogens. Their research includes fundamental studies of pathogen replication and host interactions, antimicrobial resistance, therapeutic drug design and testing, and clinical and real-time diagnostics.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

BSRC infection biologists\u2019 study basic and applied aspects of viral, bacterial and parasite pathogens. Their research includes fundamental studies of pathogen replication and host interactions, antimicrobial resistance, therapeutic drug design and testing, and clinical and real-time diagnostics.<\/p>\n","protected":false},"featured_media":137,"parent":0,"menu_order":0,"template":"","class_list":["post-93","research_theme","type-research_theme","status-publish","has-post-thumbnail","hentry"],"jetpack_sharing_enabled":true,"related_groups":[{"group_members":"

Group Leader<\/h5>\r\nDr David Hughes\r\n
Postdoctoral Research Fellow<\/h5>\r\nDr Andri Vasou\r\n
Technician<\/h5>\r\nChris Simmons-Riach\r\n
PhD Student<\/h5>\r\nAndrew Seaton - kindly funded by Tenovus\r\n\r\nChloe Jones - kindly funded by the School of Biology\r\n
Former Members<\/h5>\r\nDavid Holthaus (Masters Student - 2018)<\/span>\r\nAlethea MacPhail\u00a0 (Senior Honours Research Student - 2018)<\/span>\r\nMiroslav Botev\u00a0 (Senior Honours Research Student - 2018)<\/span>\r\nJulia Karrer\u00a0 (Masters Student - 2017)<\/span>\r\nCassie Cullen (Senior Honours Research Student - 2016)<\/span>\r\nJames Feldman (Senior Honours Research Student - 2015)<\/span>\r\nNiralini Thayaparan (Visiting Summer Student - 2015)<\/span>\r\nNatalie Penswick (Research Technician - 2013-2014)<\/span>","publications":"[publications flag='individual' code='djh25' dois='1' max='10' categorise='1']","research_projects":"
\r\n\r\nWe\u2019re fascinated by a family of proteins, known as ubiquitin-like proteins (e.g. ubiquitin, ISG15, NEDD8, SUMO), and how they shape our responses to infection. We also study how viruses manipulate the functions of these proteins, and other aspect of cell biology, for their own benefit.\u00a0<\/span>\r\n
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Virus - Host interactions<\/span><\/h2>\r\n

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Innate immunity<\/span><\/h2>\r\n

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Novel tools<\/span><\/h2>\r\n
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\r\n\r\nMajor outbreaks of childhood infections by pathogens such as the mumps and measles viruses continue to cause significant illness in young children despite the availability of effective vaccines. Additionally, infections with viruses for which there is no vaccine \u2013 such as\u00a0<\/span>parainfluenza viruses<\/a>\u00a0<\/span>- lead to significant numbers of children needing intensive care treatment in hospital. These viruses belong to a highly related group that, in addition to being clinically relevant pathogens, serve as exceptional models in the laboratory for studying how our bodies respond to viral infections \u2013 knowledge that has the potential to be translated into effective treatments.\r\n\r\nDuring our first-line defence against virus infection our cells produce factors (including proteins like\u00a0<\/span>interferon<\/a>) aimed at combating the infection. This response, known as the innate immune response, involves the expression of hundreds of genes and places significant stress on our bodies. The products of these genes work in concert to directly target the infection, to trigger the arm of the immune response that involves antibodies and T cells and to regulate the magnitude of the innate response; the latter is essential as an uncontrolled response can lead to autoinflammatory diseases.\r\n\u200b\r\nOur research<\/strong>\u00a0<\/span>aims to understand how the innate immune response is controlled and how can viruses overcome our defences - knowledge that could be used to develop more effective antiviral therapies.\r\n\r\nTechnical summary:<\/em><\/u>\r\nIn recent years, our work has focussed on understanding the interplay between virus infections and the ubiquitin-like (UbL) protein system, utilising DNA viruses (herpesviruses) and RNA viruses (particularly paramyxo- and pneumoviruses) as models. The attachment of UbL proteins to substrates represents one of the most vital posttranslational modifications in the cell and several UbLs have been identified including\u00a0<\/span>ubiquitin, NEDD8, SUMO<\/strong>\u00a0<\/span>and the interferon-inducible protein\u00a0<\/span>ISG15<\/strong>.\r\n\r\n\u200bUsing a multidisciplinary approach, including\u00a0<\/span>molecular biology, cell biology &\u00a0proteomics<\/strong>\u00a0, the objective of our research is to gain a deeper understanding of\u00a0virus-host interactions. In doing so, we may also uncover novel therapeutic targets; the primary rationale for studying drugable\u00a0cellular processes\u00a0that hinder virus biology\u00a0is the potential\u00a0to identify\u00a0<\/span>therapies that viruses find harder to develop resistance to<\/strong>.<\/span>\r\n\r\nWe recently demonstrated that for the oncogenic Kaposi\u2019s sarcoma-associated herpesvirus (KSHV), NEDDylation is critical for the maintenance of latency and reactivation of virus replication, both of which are required for the pathogenesis Kaposi\u2019s sarcoma. Furthermore, in one of the first studies to demonstrate the potential of targeting this pathway for the treatment of virally-induced malignancy, we uncovered the molecular mechanisms that underpin cytotoxicity due to the inhibition of the NEDDylation pathway (Hughes et al. 2015., PLoS Path<\/a>).\r\n\r\nMore recently, the molecular mechanisms that govern ISG15\u2019s antiviral activity, in addition to its importance as a regulator of the antiviral response, has emerged. Our TENOVUS_Scotland-funded work has recently uncovered an exciting new mechanism that inhibits paramyxovirus transcription and replication. In addition, our\u00a0Academy of Medical Sciences-funded research has begun\u00a0to dissect the ISG15-dependent mechanisms that are essential for regulated interferon signalling, including identifying previously unknown functions of ISG15.\r\n\r\nWe have also developed\u00a0<\/span>novel tools<\/strong>, currently being marketed by Avacta Life Sciences, which can be used to dissect UbL-associated pathways at the cellular level (Hughes et al., 2017. Science Signaling<\/a>;\u00a0<\/span>Tang et al. 2017, Science Signaling<\/a>). We are always\u00a0<\/span>looking for new ways<\/strong>\u00a0<\/span>that we can use our knowledge of UbLs to tell us something about how our cells function. We are currently funded by TENOVUS-Scotland to develop new genome-wide CRISPR\/Cas9 screens for improving the identification of virus restriction factors and pathways based on our genetically engineered ISG15.KO cell lines (described in\u00a0<\/span>Holthaus et al. 2020<\/a>) - see our latest\u00a0<\/span>review<\/a>.\r\n\r\n<\/div>\r\n<\/div>\r\n
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Generation of specific inhibitors of SUMO1- and SUMO2\/3-mediated protein-protein interactions using Affimer (Adhiron) technology\r\n\u200b\u200b<\/span><\/span><\/a>Hughes, D. J.,\u00a0<\/span><\/span>Tiede, C., Penswick, N., A. S. Tang, A., Trinh, C. H., Mendal, U., Zajac, K. Z., Gaule, T., Howell, G., Edwards, T. A., Duan, J., Feyfant, E., McPhereson, M. J., Tomlinson, D. C. & Whitehouse, A.\u00a0<\/span>14 Nov 2017<\/span>\u00a0<\/span>In :\u00a0Science Signaling.<\/a><\/span>\u00a0<\/span>10<\/span>,\u00a0<\/span>505<\/span>,\u00a0<\/span>14 p., eaaj2005<\/span><\/span>\u200bDatasets:<\/span><\/strong>\r\n