Figure 12. Proposed mechanism of SIRT2 up-regulation and consequence of SIRT2 inhibition on Mtb survival.

(A) Mtb infection induces the expression and translocation of SIRT2 in the nucleus where it deacetylates histone H3K18 to induce consequential changes in host transcriptome leading to decreased activation of macrophages, reduced levels of apoptosis and ROS, and increased expression of anti-inflammatory Th2-polarizing cytokines. Simultaneously, upregulation of SIRT2 in Mtb-specific T-cells specifically deacetylates and deactivates NFκB p65 leading to an anti-inflammatory response. M2 macrophages and Th2 cells preferentially generated provide a more favorable environment for Mtb survival within the host. (B) SIRT2 inhibition in Mtb-infected cells reverses the SIRT2-dependent gene expression changes enhancing the capacity of macrophages to activate T-cells. AGK2 treatment also enhances anti-mycobacterial defense forces in macrophages such as apoptosis, ROS and pro-inflammatory Th1/Th17 polarizing cytokines. Moreover, hyperacetylation of NFκB p65 in Mtb-specific activated T-cells leads to Th1/Th17-mediated pro-inflammatory immune response. Enhanced levels of protective innate and adaptive immunity in AGK2 treated cells restrict mycobacterial survival.