SIRT2 inhibition by AGK2 enhances mycobacteria-specific stem cell memory responses by modulating beta-catenin and glycolysis
Ashima Bhaskar,
Isha Pahuja,
Kriti Negi,
Akanksha Verma,
Antara Ghoshal,
Babu Mathew,
Gaurav Tripathi,
Jaswinder Singh Maras,
Shivam Chaturvedi,
Ved Prakash Dwivedi
Affiliations
Ashima Bhaskar
Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India; Corresponding author
Isha Pahuja
Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India; Department of Molecular Medicine, Jamia Hamdard University, New Delhi, India
Kriti Negi
Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
Akanksha Verma
Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
Antara Ghoshal
Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
Babu Mathew
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
Gaurav Tripathi
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
Jaswinder Singh Maras
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
Shivam Chaturvedi
Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
Ved Prakash Dwivedi
Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
Summary: 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.
