Abstract
Tuberculosis (TB) is the leading infectious killer in the world. Mycobacterium tuberculosis (Mtb), the bacteria that causes the disease, is phagocytosed by alveolar macrophages (AM) and infiltrating monocyte-derived macrophages (MDM) in the lung. Infected macrophages then upregulate effector functions through epigenetic modifications to make DNA accessible for transcription. The metabolic switch to glycolysis and the production of proinflammatory cytokines are key effector functions, governed by epigenetic changes, that are integral to the ability of the macrophage to mount an effective immune response against Mtb. We hypothesised that suberanilohydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor (HDACi), can modulate epigenetic changes upstream of the metabolic switch and support immune responses during Mtb infection. The rate of glycolysis in human MDM, infected with Mtb and treated with SAHA, was tracked in real time on the Seahorse XFe24 Analyzer. SAHA promoted glycolysis early in the response to Mtb. This was associated with significantly increased production of IL-1β and significantly reduced IL-10 in human MDM and AM. Since innate immune function directs downstream adaptive immune responses, we used SAHA-treated Mtb-infected AM or MDM in a co-culture system to stimulate T cells. Mtb-infected macrophages that had previously been treated with SAHA promoted IFN-γ, GM-CSF, and TNF co-production in responding T helper cells but did not affect cytotoxic T cells. These results indicate that SAHA promoted the early switch to glycolysis, increased IL-1β, and reduced IL-10 production in human macrophages infected with Mtb. Moreover, the elevated proinflammatory function of SAHA-treated macrophages resulted in enhanced T helper cell cytokine polyfunctionality. These data provide an in vitro proof-of-concept for the use of HDACi to modulate human immunometabolic processes in macrophages to promote innate and subsequent adaptive proinflammatory responses.
Highlights
Tuberculosis (TB) is the world’s leading infectious killer [1]
We examined the ability of the FDA-approved histone deacetylases (HDAC) inhibitor, suberanilohydroxamic acid (SAHA), to modulate early clearance events in macrophages infected with Mycobacterium tuberculosis (Mtb)
We hypothesised that the HDAC inhibitor SAHA would modulate the metabolic function of human macrophages infected with Mtb
Summary
Tuberculosis (TB) is the world’s leading infectious killer [1]. Current treatment regimens require many months of multiple drugs which are often not completed [2]. There is a significant rise in the incidence of multi-drug resistant TB, there is an urgent need for new therapeutic and vaccine strategies [1]. Mycobacterium tuberculosis (Mtb), the bacteria that causes TB, is phagocytosed by resident alveolar macrophages (AM), and infiltrating monocyte-derived macrophages (MDM) which upregulate bactericidal effector functions. These effector functions are governed by changes in chromatin structure and gene transcription [3,4,5]. Acetylation of histones opens the packed DNA to make it accessible for transcription and active, whereas HDAC close the DNA by removing acetyl groups from histones. HDAC inhibitors (HDACi) are being explored for their ability to modulate the development of TB [3, 9, 10]
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