Developing a mouse model of diabetes to evaluate vaccines for TB and melioidosis
Led by Dr Elena Stylianou (University of Oxford, UK), with Prof Helen McShane (University of Oxford, UK), Assoc Prof Susanna Dunachie (University of Oxford, UK), Assoc Prof Paul Brett (University of Nevada, USA), Dr Barbara Kronsteiner-Dobramysl (University of Oxford, UK) and Dr Panjaporn Chaichana (MORU, Thailand)
The increased susceptibility of individuals with diabetes mellitus (DM) to tuberculosis (TB) and melioidosis is well established. However there is limited understanding of the immune mechanisms behind this susceptibility, which is mainly due to an incomplete understanding of the protective immunity against both Mycobacterium tuberculosis (M.tb) and Burkholderia pseudomellei (B.p).
Similarly, very little is known about vaccine efficacy in this susceptible diabetic population. I plan to establish diabetic mouse models to investigate the effect of DM on BCG, the only licensed vaccine against TB, and two promising vaccine candidates against M.tb and B.p. I will use two complementary diabetic models that will best represent human Type 2 diabetes. First I will transfer these two models, already established in Oxford by other groups, into our laboratory. Then, animals will be vaccinated and vaccine immunogenicity and efficacy will be evaluated in control and hyperglycemic mice. In addition, this work will determine how immune cells from diabetic mice differ from control mice in their ability to generate energy in response to a vaccine.
Defining the differences in the induction of immune responses between DM and health is essential for TB and melioidosis vaccines currently in development, as these vaccines need to be effective in people that have, or may develop DM in the future.
Diabetes has been shown to alter host immune responses but there is limited information on how it affects vaccines. The project established two complementary mouse models of hyperglycaemia that best represent human type 2 diabetes to study its effects on TB and melioidosis vaccine responses. In one model, animals are fed high fat diet and in the second model, mice become hyperglycaemic upon induction. Data generated showed that animals on higher fat diets were able to better control mycobacteria in vitro, compared to mice on control diets. In addition, both vaccine immune responses and efficacy were improved with higher fat diets. On-going work is investigating whether this is also true for hyperglycaemic transgenic mice. Further work will explore the in vivo efficacy of these models.