Metformin potentiates BCG efficacy against Mtb infection

Abstract

Abstract Tuberculosis (TB) is a chronic inflammatory disease that is caused by the bacterium Mycobacterium tuberculosis (Mtb) and is currently the leading cause of death by an infectious disease worldwide. Presently, TB therapeutic strategies include prolonged treatments with antimicrobial drugs, which often produce toxic side-effects, and vaccination with Bacille Calmette-Guérin (BCG), the only available and only partially protective TB vaccine. Considering the critical need for better prevention strategies, there have been multiple attempts to enhance the efficacy of BCG, yet none have significantly outperformed BCG alone. Previously, we have demonstrated that the anti-diabetic drug, metformin, has immunomodulatory effects and is associated with increased host resistance against TB. Based on our findings we hypothesized that following BCG vaccination, treatment with metformin would also enhance the vaccine response to Mtb. To test our hypothesis, we vaccinated guinea pigs with BCG Pasteur, dosed them with metformin or mock treatment, and performed low dose aerosol infection with Mtb H37Rv. At 90 days following infection, histological evaluation revealed that guinea pigs that received metformin- BCG had significantly reduced lung lesion burden compared to BCG alone. In addition, we evaluated the effects of metformin on T cell differentiation using an in vitro model of anti-CD3/anti-CD28 activation and found that metformin enhances memory T cell marker expression. Moreover, we show that mitochondrial hyperpolarization, a critical component of T cell activation, is dampened by metformin, which may ultimately alter T cell differentiation towards a memory-like phenotype and help explain metformin’s protective efficacy.