Abstract
Mycobacterium tuberculosis (Mtb) employs plethora of mechanisms to hijack the host defence machinery for its successful survival, proliferation and persistence. Here, we show that Mtb 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, in Mtb specific T cells, SIRT2 deacetylates NFκB-p65 at K310 to modulate T helper cell differentiation. Pharmacological inhibition of SIRT2 restricts the intracellular growth of both drug-sensitive and resistant strains of Mtb 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 increased Mtb-specific protective immune responses. Overall, this study provides a link between Mtb infection, epigenetics and host immune response, which can be exploited to achieve therapeutic benefits.
Highlights
Tuberculosis (TB), a deadly disease caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), has existed since time immemorial and continues to remain one of the leading causes of mortality by a single infectious agent (WHO, 2018)
To delve into the epigenetic modifications induced by Mtb to evade host defence system, we evaluated the expression of all known histone deacetylases (HDACs) in THP1 cells 24 hr post Mtb infection through microarray analysis (Mehta et al, 2016), Gene Expression Omnibus series accession number GSE65714
The increase in the expression of Sirtuin 2 (SIRT2) following Mtb infection was further confirmed in mouse peritoneal macrophages by qRT-PCR (Figure 1B) and intracellular staining with a-SIRT2 followed by flow cytometry (Figure 1C and D)
Summary
Tuberculosis (TB), a deadly disease caused by the intracellular pathogen Mtb, has existed since time immemorial and continues to remain one of the leading causes of mortality by a single infectious agent (WHO, 2018). Mtb is known to restrict the killing capacity of macrophages by inhibiting host generated oxidative stress, apoptosis and multiple stages of autophagy (Krakauer, 2019; Lam et al, 2017). It influences the adaptive immune response by promoting the secretion of T helper 2 (Th2) polarizing cytokines (Bhattacharya et al, 2014). Mtb infection significantly changes the transcriptional landscape of host cells (Roy et al, 2018) by secreting a plethora of virulence factors to carry out these functions
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