Surveying the Epigenetic Landscape of Tuberculosis in Alveolar Macrophages

Abstract

Tuberculosis (TB) remains the leading cause of bacterial disease-related death and is among the top 10 overall causes of death worldwide. The complex nature of this infectious lung disease has proven difficult to treat, and significant research efforts are now evaluating the feasibility of host-directed, adjunctive therapies. An attractive approach in host-directed therapy targets host epigenetics, or gene regulation, to redirect the immune response in a host-beneficial manner. Substantial evidence exists demonstrating that host epigenetics are dysregulated during TB and that epigenetic-based therapies may be highly effective to treat TB. However, the caveat is that much of the knowledge that exists on the modulation of the host epigenome during TB has been gained using in vitro, small-animal, or blood-derived cell models, which do not accurately reflect the pulmonary nature of the disease. In humans, the first and major target cells of Mycobacterium tuberculosis are alveolar macrophages (AM). As such, their response to infection and treatment is clinically relevant and ultimately drives the outcome of disease. In this review, we compare the fundamental differences between AM and circulating monocyte-derived macrophages in the context of TB and summarize the recent advances in elucidating the epigenomes of these cells, including changes to the transcriptome, DNA methylome, and chromatin architecture. We will also discuss trained immunity in AM as a new and emerging field in TB research and provide some perspectives for the translational potential of targeting host epigenetics as an alternative TB therapy.

Keywords: DNA methylation; Mycobacterium; alveolar macrophages; epigenetics; histone modifications; host-directed therapy; lung immune cells; trained immunity; tuberculosis.

FIG 1

Alveolar macrophages are distinct from blood-derived macrophages. At steady state, AM (left) express different surface markers and metabolic programs than macrophages derived from circulating monocytes (right). Surface markers CD11c, CD200R, TGF-βR, IL-10R, and CD169 are highly expressed on AM, whereas inflammatory M1 blood-derived MDM express CD11b and CD14. CD64 and SIRP-α are expressed by both cell types, but on AM, SIRP-α is activated by lung surfactant proteins. AM rely primarily on oxidative phosphorylation to thrive in an oxygen-rich environment, but circulating macrophages use glycolysis. AM also have an increased capacity for lipid metabolism, which can impair IL-4 signaling. At the epigenetic level, AM development at birth is regulated by PPARγ and BACH2, whereas circulating blood-derived MDM development is regulated by NUR77. AM are epigenetically programmed to have unique TF and cytokine expression profiles. During M. tuberculosis infection, the immune response of AM is delayed compared to that of MDM, which in mice is mediated by the TF NRF2. Blood-derived MDM are cleared from the site of infection through FAS-mediated apoptosis, whereas AM express low levels of FAS, facilitating their survival postinfection.

FIG 2

Epigenetic modifications in alveolar macrophages infected with M. tuberculosis. Infection of AM by M. tuberculosis or M. bovis triggers histone modifications (acetylation or methylation) and DNA methylation to alter the antibacterial immune response. In bAM, increased H3K4me3, a mark of gene activation, at specific gene promoters results in increased expression of RIG-I, AKT, ARG2, and BCL2A. RIG-I contributes to the type I IFN response. AKT and ARG2 promote M2 polarization, and BCL2A is a negative regulator of apoptosis. In M. tuberculosis-infected hAM, the proinflammatory immune response is regulated by HDACs. Accordingly, treatment with a pan-HDAC inhibitor increased levels of IL-1β and decreased levels of IL-10, while inhibition of HDAC3 enhanced bacterial clearance in hAM. HDAC inhibition also increased glycolysis in infected hAM and, together with inflammation, led to enhanced T helper cell responses by stimulating these cells to produce more IFN-γ, GM-CSF, and TNF-α. M. tuberculosis infection of hAM also induced global changes in chromatin accessibility, leading to increased accessibility and the H3K27ac activation mark in the promoters of genes involved in type I IFN responses. This corroborates the host-detrimental effect of type I IFN in TB that is known to block glycolytic metabolism and IFN-γ signaling and induce mitochondrial stress. The DNA methylome signature, another type of epigenetic modification that is associated with gene repression, is also altered in AM from individuals with latent or active TB or those who were contacts of TB patients. The altered methylome signatures were enriched in pathways involving vitamin D metabolism (VD), pentose phosphate pathway (PPP), RAS, p38, or HIF1-α, the latter of which is known to induce glycolytic metabolism in an IFN-γ-dependent mechanism during M. tuberculosis infection.

FIG 3

Alveolar macrophages are reprogrammed by trained immunity. Pulmonary BCG or Ad-TB vaccination in mice induced the activation of AM to have sustained antibacterial functions that provide host protective immune responses against M. tuberculosis challenge for up to 7 months. This reprogramming, known as trained immunity, is driven by epigenetic modifications that result in the upregulation of multiple genes and proteins involved in inflammation and metabolism, including Nos2, Ifnγ, Ldlr, CD86, and MHC-II. AM reprogrammed through trained immunity display a shift in metabolism from oxidative phosphorylation to increased glycolysis and increased capacity to kill intracellular M. tuberculosis through the upregulation of iNOS and other antibacterial pathways. However, the specific epigenetic modifications and mechanisms involved in the control of these genes, proteins, and pathways have yet to be determined in AM.