Dr Barbara Kronsteiner-Dobramysl
University of Oxford, UK
Diabetes alters cellular metabolism of T cells: implications for vaccine development
Diabetes (DM) is a serious global health problem currently affecting over 415 million people worldwide. Relationships between DM and a range of global pathogens have been reported, including tuberculosis, Hepatitis and dengue. With a 12-fold increased risk, the biggest impact of DM on acquiring infection is seen for melioidosis, a neglected tropical disease caused by the Gram-negative bacterium Burkholderia pseudomallei (BP). The high circulation levels of blood glucose and free fatty acids in type 2 diabetes generate a deregulated energy reservoir. The aim of this study is to determine how these systemic changes affect the metabolic capacity and function of circulating immune cells specifically focusing on T cells. We are studying cellular metabolic changes in peripheral blood mononuclear cells (PBMC) of Thai melioidosis patients and endemic controls with and without DM using extracellular flux analysis (Seahorse, Agilent) and flow cytometry. PBMC from recovered melioidosis patients re-stimulated with cognate antigen showed impaired spare respiratory capacity. In endemic controls we observed lower baseline levels of mitochondrial respiration and decreased glycolytic capacity in TCR+αCD28 activated PBMC from people with DM compared to nonDM. Furthermore, T cells and NK cells from people with DM had higher uptake of fatty acids (FA) and increased expression of the FA receptor CD36 upon TCR activation. Ongoing work is evaluating further differences in fuel utilization, metabolic flux and mitochondrial biogenesis in CD4+ and CD8+ T cells upon TCR activation with the aim to identify drug-able pathways (e.g. AMPK-Metformin) to improve cellular metabolism and eventually vaccine-induced memory responses.
I hold a doctoral degree in immunology from the University of Salzburg, Austria and have 5 years of postdoctoral research experience based at US and UK universities. Since the beginning of 2016, I am working with Prof. Susanna Dunachie at the Centre for Tropical Medicine and Global Health, University of Oxford, on defining immune correlates of survival and protection in human melioidosis as well as the susceptibility of diabetics to infection. In my current research projects I am focusing on metabolic changes in immune cells from people with diabetes and how this contributes to delayed and dysfunctional immune responses as well as poor vaccine efficacy. I am highly experienced in multicolour flow cytometry, mammalian cell culture techniques and immunological assays, work with human and mouse primary cells as well as metabolic assays including extracellular flux analysis using Seahorse.