Host Sirtuin 2 as an immunotherapeutic target against tuberculosis

Mycobacterium tuberculosis (Mtb) employs plethora of mechanisms to hijack the host defence machinery for its successful survival, proliferation and persistence. Here we show thatMtb upregulates one of the key epigenetic modulators, NAD+ dependent histone deacetylase Sirtuin 2 (SIRT2), which upon infection translocate to the nucleus and deacetylates histone H3K18, thus modulating the host transcriptome leading to enhanced macrophage activation. Furthermore, inMtb specific T cells, SIRT2 deacetylates NF κB-p65 at K310 to modulate T helper cell differentiation. Pharmacological inhibition of SIRT2 restricts the intracellular growth of both drug-sensitive and resistant strains ofMtb and enhances the efficacy of front line anti-TB drug Isoniazid in the murine model of infection. SIRT2 inhibitor-treated mice display reduced bacillary load, decreased disease pathology and increasedMtb specific protective immune responses. Overall, this study provides a link betweenMtb infection, epigenetics and host immune response, which can be exploited to achieve therapeutic benefits.
Source: eLife - Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research