Title: Correlates of Protective Immunity and Immunopathology for Dengue in Obesity and Normal weight
Funder: The Academy of Medical Sciences

Abstract: Dengue virus (DENV) is transmitted by mosquitoes and circulates as four serotypes which infect 390 million people per year. There are no therapies for dengue and the first dengue vaccine is only partially protective despite its ability to induce neutralizing antibodies against all four DENV serotypes. Dengue infections cause a range of clinical symptoms from a mild fever to more severe syndromes, which in some patients can lead to life-threatening haemorrhagic shock. Several risk factors have been identified for severe dengue, including a previous dengue infection, age and overweight/obesity. The host immune response is believed to contribute to DENV pathology, with studies showing a role of pre-existing antibodies in enhancing infection and others suggesting a role of T and NK-cells. The interplay between T, B and NK-cell responses in determining protective immunity to dengue as well the mechanisms leading to immunopathology remain elusive. The aim of this proposal is to identify novel “integrated” correlates of protective immunity/immunopathology for dengue by analysing T, NK, B-cells and antibodies in a matched cohort of normal weight and overweight/obese dengue patients. We hypothesize that T and NK-cells play a critical role in orchestrating the immune response to dengue and that impairment of these cells underlies the increased susceptibility of overweight/obese individuals to severe dengue. This study will be relevant for other inflammatory viral diseases (e.g. COVID-19) and pave the way towards a paradigm shift from an antibody only-based definition of immune protection/immunopathology towards a more comprehensive one that integrates key anti-viral immune cells.

Lay abstract: Dengue virus is transmitted by mosquitoes and infects 390 million people per year. There is no cure for dengue and the first dengue vaccine is not very effective. Dengue infections cause a range of clinical symptoms from a mild fever to more severe syndromes which can potentially be life-threatening. Recently there has been evidence that overweight/obese people are more likely to suffer severe disease symptoms. The reasons underlying this risk are unclear but may relate to the altered immune responses of obese people. Studies have shown that severe disease is caused by an aberrant immune response to dengue virus, but the contribution of the different immune cells remains unclear. This proposal aims to understand the role played by two types of immune cells called T and NK-cells - which can kill virus-infected cells - during dengue infection. We aim to provide a more comprehensive understanding of immunological features that protect from, as well as those that lead to, development of severe dengue in dengue patients that are overweight/obese or have healthy weight. We hypothesize that T and NK-cells are unable to perform their anti-viral functions during severe dengue, and that these processes are more pronounced in obese/overweight patients, thus making them more at risk of severe dengue. These results will be relevant for other inflammatory viral diseases (e.g. COVID-19) and will give insights into what the immune response looks like in dengue patients with mild versus severe life-threatening disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: INFECTION