Dissecting global protective immune response to dengue virus at a single-cell resolution

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Dengue virus (DENV) infection is a mosquito-borne disease that infects 390 million people each year. Despite a sharp rise in the number of infected case over the past decade, there is currently no available specific treatment. A vaccine has been developed but is of limited efficacy and has been shown to cause severe side-effects when given to young children. It has been observed that some individuals who are infected with the virus either develop no or very mild symptoms and clear the virus, whereas other individuals develop fever and severe symptoms such as bleeding and shock. Here we aim to compare infected individuals with and without these harmful symptoms to better understand which parts of the immune systems are responsible for clearing the virus and which parts are responsible for causing the often very severe symptoms without clearing the virus effectively. Human "innate" immune response reacts to general danger signals such as those generated during a viral infection, whereas the "adaptive" immune response recognises the shape of an invader and mount a specific response against this. B and T lymphocytes are the mediators of the adaptive immune response. Each individual T and B lymphocyte carries a unique receptor that is able to recognise a different shape on the infectious agent. Therefore, ideally, immune responses need to be studied at the level of the single cell. At the Wellcome Trust Sanger Institute (WTSI UK), cutting-edge technology has recently been developed that is able to profile immune cells at the single cell level. Complex "transcriptomics" data are generated, and computational tools for the successful analysis of this type of large-scale data have only recently been developed. We now propose to apply single cell profiling techniques to one of the most comprehensive Dengue patient cohort assembled in Thailand, one of the main hubs of dengue cases By identifying specific differences in the immune response of individuals with and without disease, we will (1) identify the specific cell subtypes of both the innate and adaptive immune response that is responsible for clearing the virus, (2) provide a molecular description of the receptors in B and T cells that are able to bind the virus. The knowledge gained will help to develop more effective vaccines and anti-viral treatments. In addition, the project will allow Mahidol University (MU, Thailand) to develop a single-cell analysis platform that can be applied to study other infectious diseases in the future.