Impact of obesity and diabetes on immune responses to SARS-CoV-2 in Bangladeshi adults

Overweight/obesity (Ov/Ob) and diabetes mellitus (DM) are known as independent risk factors for severe COVID-19 outcomes, which disproportionately affect the South Asian population. South Asians with a body mass index (BMI) of 27 kg/m2 have the same risk of COVID-19 mortality as white ethnicities at a BMI of 40 kg/m2. This thesis investigates the effects of Ov/Ob and DM on humoral and cellular immune responses to SARS-CoV-2 in 198 individuals during the first pandemic wave prior to the global rollout of vaccines in Bangladesh. The study cohorts include healthy controls (n=63), individuals with severe acute COVID-19 (n=60), and those who have recovered from COVID-19 (n=75). A variety of immunoassays were performed, including the Meso Scale Discovery (MSD) immunoassay, B cell FluoroSpot, Focus Reduction Neutralisation assay for antibody responses, and IFN-γ ELISpot, intracellular cytokine staining, and proliferation assays for T cell responses. Acute patients with Ov/Ob (BMI ≥ 23 kg/m2) demonstrated higher levels of IgG responses to the SARS-CoV-2 spike compared to those without Ov/Ob. Following COVID-19 recovery, individuals with Ov/Ob displayed reduced neutralising antibody capacity against SARS-CoV-2 despite comparable IgG responses, alongside increased anti-SARS-CoV-2 IFN-γ responses, CD8+ T cell proliferation, and IL-2 production compared to those without Ov/Ob. DM was not associated with antibody and T cell responses in acute infection and recovery. Single-cell transcriptomic analysis of resting peripheral blood mononuclear cells from 11 COVID-19 survivors with and without DM revealed distinctive transcriptomic profiles marked by significant upregulation of immune activation pathways and metabolic reprogramming in DM across major immune cell types. T cells in DM showed upregulation in Th1 and Th17 differentiation pathways and oxidative phosphorylation. NK cell-mediated cytotoxicity as well as antigen processing and presentation by monocytes were upregulated in DM. B cells showed a metabolic shift towards glycolysis and a Th2 immune response under DM conditions. Collectively, the work presented in this thesis advances our understanding of the adaptive immune response to SARS-CoV-2 in individuals with metabolic diseases. This biological insight paves the way for future studies to improve the management of not only COVID-19 but also future pandemics, ensuring better outcomes for patients burdened with comorbidities such as Ov/Ob and DM.