SIRT2 inhibition by AGK2 enhances mycobacteria-specific stem cell memory responses by modulating beta-catenin and glycolysis

• DOI: 10.1016/j.isci.2023.106644
• Publication Date: 2023-04-10T15:54:01Z
• Authors: Ashima Bhaskar; Isha Pahuja; Kriti Negi; Akanksha Verma; Antara Ghoshal; Babu Mathew; Gaurav Tripathi; Jaswinder Singh M...; Shivam Chaturvedi; Ved Prakash Dwivedi
• Keywords: Science; Immunology; Q; Bacteriology; Article; 3. Good health

Bacille Calmette-Guerin (BCG) generates limited long-lasting adaptive memory responses leading to short-lived protection against adult pulmonary tuberculosis (TB). Here, we show that host sirtuin 2 (SIRT2) inhibition by AGK2 significantly enhances the BCG vaccine efficacy during primary infection and TB recurrence through enhanced stem cell memory (TSCM) responses. SIRT2 inhibition modulated the proteome landscape of CD4+ T cells affecting pathways involved in cellular metabolism and T-cell differentiation. Precisely, AGK2 treatment enriched the IFNγ-producing TSCM cells by activating β-catenin and glycolysis. Furthermore, SIRT2 specifically targeted histone H3 and NF-κB p65 to induce proinflammatory responses. Finally, inhibition of the Wnt/β-catenin pathway abolished the protective effects of AGK2 treatment during BCG vaccination. Taken together, this study provides a direct link between BCG vaccination, epigenetics, and memory immune responses. We identify SIRT2 as a key regulator of memory T cells during BCG vaccination and project SIRT2 inhibitors as potential immunoprophylaxis against TB.