Surveying the Epigenetic Landscape of Tuberculosis in Alveolar Macrophages
Special Series: Minireviews from Early-Career Investigators
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.
INTRODUCTION
Tuberculosis (TB) has plagued humanity for millennia and, until the coronavirus 2019 (COVID-19) pandemic, was the leading cause of death from a single infectious agent, ranking above HIV/AIDS (1). The persisting prevalence of TB reflects the strikingly complex nature of the disease despite modern medical advances. Treatment for TB is still limited to multiple combinations of antibiotics that require months of therapy, and can lead to side effects. Tuberculosis treatment regimens have been associated with low patient compliance, which can result in the development of drug resistance. In 2020, there were approximately 500,000 cases of drug-resistant TB worldwide (1). As such, the development of alternative adjunctive therapies that boost host immunity to TB is highly desirable and a focus for current TB research. Targeting of host cell processes such as autophagy and cholesterol metabolism to treat TB has gained success in preclinical and early-phase clinical trials, demonstrating the promise of host-directed therapy (2–6). However, the success of advancing these and other host-directed therapies for TB will require a complete understanding of the diverse and complex nature of the human immune response to TB.
TB occurs when the intracellular pathogen Mycobacterium tuberculosis is inhaled and infects alveolar macrophages (AM) and neutrophils in the lung, wherein it forms its replicative niche (7, 8). Successful infection by M. tuberculosis depends on the reprogramming of host immune cells to evade antibacterial mechanisms and dampen the immune response while simultaneously maintaining host cell viability. Hallmarks of host immunoevasion by M. tuberculosis include dysregulated phagocytosis, production of reactive oxygen and nitrogen species, autophagy, apoptosis and other cell death pathways, antigen presentation, metabolism, and macrophage polarization (9, 10).
Extensive research into genetic predispositions that increase the susceptibility to TB have failed to uncover specific functional genes that are associated with susceptibility to TB (11, 12). Rather, reports show that alterations at the gene expression level are responsible for susceptibility to TB (13, 14). This suggests that variations in the epigenome, rather than the genome, potentiate host susceptibility to TB (15). This notion is compelling given that epigenetic alterations have recently been linked to both bacterial and viral infectious diseases (16, 17). Epigenetics are changes in the activity, expression, or function of genes that are not mediated by DNA sequence. Most often, epigenetic changes involve accessibility of the DNA to the transcriptional machinery, which is regulated by mechanisms such as DNA methylation, nucleosome or histone modifications, and transcription factor (TF) binding. Indeed, there are growing reports that M. tuberculosis infection changes how DNA is packaged at specific genes, thereby altering the epigenome (12, 15).
Despite the advances in our understanding of the role of epigenetics in TB, an important limitation of many of these studies is the reliance on cell lines and blood-derived macrophage models. M. tuberculosis specifically targets lung-resident macrophages and neutrophils in vivo to build its replicative niche during the initial weeks of infection (7, 18). Dissemination of the bacteria depends on the capacity of alveolar macrophages to contain the infection and ultimately determines the clinical manifestation of TB (7). Given that immune cells in the lung microenvironment are functionally and phenotypically distinct compared to circulating immune cells, alveolar macrophages represent the most physiologically and clinically relevant host cell to study epigenetics in TB. The TB research community is aware of the shortcomings of overreliance on blood monocyte/macrophage model systems; hence, there is a growing body of studies that incorporate primary lung cell models to study host epigenetics in TB. This is enabled by the rapid advancement of genome-wide techniques, including the assay for transposase-accessible chromatin sequencing (ATAC-seq), cleavage under targets and tagmentation (CUT&Tag), improved whole-genome bisulfite sequencing methods, and innovative single-cell platforms, like single-cell genome and epigenome by transposase sequencing (scGET-seq) (19–22), that remove the limitation for large cell numbers. In this minireview, we highlight the specialized phenotype and function of alveolar macrophages, provide a comprehensive summary of epigenomic profiling studies in the context of TB that use primary lung immune cells, and discuss how this knowledge may lead to translation from bench to bedside.
EVIDENCE OF EPIGENETIC MODIFICTIONS DURING M. TUBERCULOSIS INFECTION
An extensive number of studies have demonstrated the existence and impact of epigenetic changes at the level of histone modifications that are induced by M. tuberculosis infection (23–27). Indeed, in vitro models have shown that epigenetic regulation of several host immune response pathways during M. tuberculosis infection occurs through alterations to nucleosome structure (23, 24). The histone marker H3K4me3, indicative of active promoters, is enriched at genes that negatively regulate reactive oxygen species (ROS) production following infection with virulent M. tuberculosis compared to attenuated M. tuberculosis (23). These genes include ATF2, DUSP4, SATB1, IRF3, and PRKCD. SET8-induced H4K20me led to the upregulation of Nqo1 and Trxr1 during M. tuberculosis infection, which promoted the polarization of AM toward an anti-inflammatory (M2) state and dampened the immune response (24). Furthermore, the H3K27me3 demethylase JMJD3 is reported to promote foamy macrophage proliferation after infection (28). Genome-wide analyses of Mycobacterium bovis infection have also shown increased promoter accessibility on genes that negatively regulate ROS production or tumor necrosis factor alpha (TNF-α)-induced apoptosis, and genes that promote M2 macrophage polarization (29). The expression of histone deacetylases (HDAC1 and HDAC3) and sirtuins (SIRT1 and SIRT3) is up- and downregulated, respectively, to modulate several M. tuberculosis response pathways that promote bacterial survival and trigger host pathology (26, 30–36). Similarly, genome-wide DNA methylation analysis of the human monocytic cell line THP-1 and peripheral blood monocyte-derived macrophages (MDM) has shown that changes to DNA methylation also regulate the immune response to M. tuberculosis (37, 38). Differential DNA methylation regulated AMPK signaling pathways in MDM and interleukin-6R (IL-6R), IL4R, and IL-17R in THP-1 cells. While all the studies described in this section have exclusively relied on cell lines and blood-derived macrophage models, they nevertheless established a key role of epigenetic mechanisms in dampening host immunity to M. tuberculosis infection.
ALVEOLAR MACROPHAGES ARE DISTINCT FROM BLOOD-DERIVED MACROPHAGES
Immune cells in the lung.
The innate immune cells of the lungs are required to defend the airways from the host’s external environment and thus have many specialized functions compared to their counterparts in the blood or other tissues. The major types of immune cells that patrol the airways are macrophages, neutrophils, eosinophils, and lymphocytes, although macrophages and neutrophils form the majority. In samples of pulmonary fluid obtained through bronchoalveolar lavage, greater than 80% of cells present are macrophages, while lymphocytes are found in the range of 3 to 15%, neutrophils are less than 2%, and eosinophils are less than 1% (39–42). This composition varies slightly in samples obtained through sputum induction, where the immune cell population is comprised of 40 to 80% macrophages, 30 to 60% neutrophils, less than 10% eosinophils, and less than 5% lymphocytes (39–42). As such, alveolar macrophages and neutrophils are the first responders to infection, and their immune response is a critical step in determining the outcome of disease. The role of lung neutrophils in TB is inconclusive. They are largely negatively associated with disease pathogenicity and bacterial clearance but recently have been shown to contribute to protection in macaque infection models (43, 44). It has been proposed that neutrophils also contribute to TB resistance depending on ratios of their subpopulations (8). The precise role and contribution of neutrophils to TB pathogenesis remains unresolved due to the difficulty of obtaining primary, viable neutrophils, especially those residing in the lung. Given the limited number of studies using primary lung neutrophils, this review will focus on epigenetic signatures in alveolar macrophages during M. tuberculosis infection.
Alveolar macrophages.
Despite sharing an origin in the myeloid lineage, AM diverge from blood monocytes in the first stages of development, after which they are committed to the lung as tissue-resident macrophages (45–49). The lung environment programs AM at the epigenetic level to generate a subset of macrophages with unique gene and TF expression profiles, including enrichment of inflammatory NF-κB-regulated genes and genes regulating lipid metabolism (50–52). The resulting phenotype is a hybrid of classically (M1) and alternatively (M2) activated macrophages, which differs from blood-derived macrophages by their surface marker expression and inflammatory cytokine production (48, 50, 53) (Fig. 1). Specifically, AM express CD11c, CD200R, IL-10R, and TGF-βR but also classically expressed markers such as CD64, CD14, CD206, SIRP-α, and MerTK that are found on MDM (45, 53–56). CD200R, IL-10R, and TGF-βR respond to their corresponding agonists to regulate the inflammatory response, whereas SIRP-α in AM responds to lung surfactant proteins to specifically prevent lipopolysaccharide-induced inflammation and prevent phagocytosis (56–59). Overall, these mechanisms serve to prevent damaging inflammation in the lung. AM are reported to have significantly lower expression of the FAS death receptor than circulating MDM, such that following infection, AM are maintained in the lung whereas recruited MDM are lost due to cell death (60). However, in many disease models, it has been shown that the remaining AM have reduced proinflammatory capacity (61). Interestingly, AM are programmed to use oxidative phosphorylation to thrive in the oxygen-rich lung, whereas inflammatory MDM normally rely on glycolysis as their main source of energy (62) (Fig. 1). Restricted glycolysis and increased lipid metabolism have further been shown in mice to benefit M. tuberculosis and prevent AM from responding to IL-4 stimulation, which also impaired macrophage polarization (63, 64) (Fig. 1).
FIG 1
As a result of the epigenetic and functional differences between AM and MDM, AM often produce distinct immune responses to infection. In mice, resident AM and recruited macrophages have distinct gene expression and metabolic profiles that result in notably different immune responses, such that AM are more permissive hosts to M. tuberculosis (62, 64, 65). In line with this, gene set-specific expression (Ampli-seq) analysis revealed that several of the most highly differentially expressed genes (DEG) between AM and MDM at baseline are indeed components of M. tuberculosis response pathways (66). Following M. tuberculosis infection, the number, timing, and subset of DEG were notably different between AM and MDM (66, 67). Between 2 and 24 h postinfection, the comparative number of significant DEG between MDM and AM decreased from 40-fold to 1.7-fold, respectively, and then increased again to 25-fold at 72 h postinfection, clearly demonstrating the delayed immune response characteristic of AM (66). Table 1 provides a list of highlighted genes. Conversely, in bovine AM (bAM), the total number of DEG was approximately 2-fold greater than in MDM, and the overlap of similar genes was 22% (67). In an in vivo murine model, inflammation was substantially impaired in AM compared to MDM, which permitted bacterial replication and dissemination (18). The delayed immune response of infected AM was driven by the TF NRF2, which upregulates the production of antioxidants and downregulates major histocompatibility complex class II (MHC-II) expression to impair macrophage activation (18, 68) (Fig. 1). The permissive nature of AM to M. tuberculosis infection was further reported to be derived from the specific epigenotype of these cells (65, 69). Collectively, there is compelling evidence that AM are significantly different cells than macrophages derived from circulating monocytes, specifically in their response to pathogens.
TABLE 1
| Method | Model | Differentially expressed genes | Functional pathways | Reference |
|---|---|---|---|---|
| Transcriptomic | ||||
| Microarray | Healthy hAM infected ex vivo | CXCL1,5, HCK, KYNU, GBP2, IFNGR2, CABLES1, TBC1D2, TNFRSF2 | IFN-γ response | 73 |
| TB hAM infected ex vivo | IRF1, AIM2, IFIT2,3, MX1, HELZ2, EPSTI1, CSRNP1, CXCL9, SOCS1 | Type I IFN, inflammasome | ||
| Microarray | Healthy hAM vs TB hAM | CHIT1, CHI3L1, CCL5,8,22, CXCL5,9, MMP7,9,12, CCND1,2, CCNA1, IL1B, CAMP, TGFB1, MARCO COLEC12, CES1 | Proliferation, phagocytosis, tissue damage | 75 |
| RNA-seq | bAM infected ex vivo | Tlr2,4, Cd14, Myd88, Ddx58, Ifih1, Dhx58, Mavs, Casp7,8, Bid, Cycs, Bcl2a1,2,2l1, Cflar, Birc2,3, Xiap, Mcl1, Prkx, Endog, Dffa, Aifm1, Sumf1, Gnptab, Igf2r | Type I IFN, apoptosis, lysosome | 67 |
| Metabolic flux analysis | mAM and IFNAR−/− AM infected in vivo | NA | Increased glycolysis in IFNAR−/− AM | 74 |
| Dual host-microbe RNA-seq | mAM infected in vivo | Mgl, Lpl, LipA, Dhcr7, Lpin1, PPAR-γ, Gsta3, Prdx1, Srxn1, Hmox1, Sqstm1 | Lipid metabolism, cell division, NRF2 response | 65 |
| RNA-seq | bAM infected ex vivo | Abca5, Abca6, Abca10 Abcg1, Abca1, Acat1 | Cholesterol metabolism, autophagy | 76 |
| qRT-PCR | Healthy hAM infected ex vivo | NOD2 | Autophagy | 77 |
| RNA-seq, ChIP-seq | mAM infected in vivo, 10 days | Nqo1, Cat, Prdx1, Txnrd, Hmox1, Gstm1, Gclm, Gsta3, Me1, Trem1, CCR1, MMP8, CIITA, L1a, Tnf, Rel, Relb, Nfkb2, Ccl2,17, Bhlhe40, Nfe2l2, Tnf, Il1a, Cxcl2,13 | NRF2 response, proinflammatory response | 18 |
| Ampli-Seq | Healthy hAM infected ex vivo, 2 h, 24 h, 72 h | IFNG, MT1L, CRNKL1, CXCL2,3, CCL20, PTX3, CSF2, IL-1β, JUN, IL-6, IER3, SERPINB2, CFL1, CLIC1, CTSL, CXCL5, FLNA, IL1RN, SERPINB2 TMBIM6 YBX1, TNF, IL2A, CCL20, CXCL9, STAT1, PTGS2 | IL-10 pathways, TREM1 signaling, IFN signaling | 66 |
| qRT-PCR | PPAR-γ−/− mAM infected ex vivo | IL-10, TNF, IL-6, IL-1β | Proinflammatory response | 78 |
| RNA-seq | Healthy infant hAM infected ex vivo, healthy adult hAM infected ex vivo | JAK2, STAT1, CYBB, DRAM2, UVRAG, ACP5, FUCA1, ABCA2, CCL2,7,8,13, CXCL1,2,5,6,8,9,10,11, PPBP, TLR3, FCGR1B, SIDT2, ABCA2, CCL8,10,11,13 | Lysosomal maturation, IFN-γ response, mycobacterial activity | 79 |
| DNA me | ||||
| RRB-seq | Healthy and latent TB hAM | NA | Pentose Phosphate, Ras signaling | 83 |
| Illumina BeadChip | Healthy, TB contact and TB patient hAM | NA | Vitamin D metabolism, HIF1-α, P38 signaling | 84 |
| Whole-genome bisulfate sequencing | bAM infected ex vivo | Hdac5, Kdm2b, Ezh1, Prdm2, Setmar, Smyd4, Usp12 Intermediate methylation: IL-12RA, C1qb | Chromatin modifiers, NADH dehydrogenase | 87 |
| Histone ac/me | ||||
| RNA-seq, ATAC-seq, ChIP-seq | Healthy hAM infected ex vivo | CXCL10, IFI44L, APOBEC3A, MX1 | IFN, TNF, NLR, TLR, NF-κB signaling | 89 |
| RNA-seq, ChIP-seq | bAM infected ex vivo | Arg2, Bcla2, Sting, Stat1, Osm, Csf3, Cntfr, Irf7, Rac1, Pik3ap1, Trim25, Isg15, Ikbke | PI3/AKT, RIG-I, JAK-STAT signaling | 29 |
| ELISA | Healthy hAM infected ex vivo + SAHA | IL-1β, IL-10, | Increased glycolysis, CD4 Th cell response | 92 |
| ELISA | Healthy hAM infected ex vivo + RGFP9966 | IL-1β, IL-6, TNF | Enhanced antibacterial response | 30 |
| Trained immunity | ||||
| ELISA | Healthy hAM ± BCG vaccination | HLA-DR, CD11b | Reduced activation | 103 |
| FACS, RNA-seq | mAM ± pulmonary BCG vaccination | MHC-II, CD68, iNOS, Nos2, Ifng, Irf8, Ccl2, Hk2, Ldlr, G6pdx, Ldha | Macrophage activation, metabolism | 103 |
| M. tuberculosis killing assays, Metabolic assays, ELISA | mAM ± pulmonary Ad-TB vaccination | MHC-II | Enhanced bacterial killing, macrophage activation, increased glycolysis | 108 |
| ELISA, RNA-seq, ATAC-seq | mAM ± contained M. tuberculosis infection | IL-6, Stat1, Stat3, Jak1, Jak2, Tnfaip2, Ifng | Enhanced bacterial killing, inflammation, IFN-γ pathways, IFN-α pathways | 109 |
| M. tuberculosis killing assays, ELISA, cytokine PCR array | mAM and neutrophils infected ex vivo after BCG vaccination | NA | Enhanced bacterial killing, protective neutrophil response | 110 |
| FACS, M. tuberculosis killing assays | Mouse neutrophils after BCG vaccination and M. tuberculosis challenge | NA | Neutrophil activation, Th1 response | 111 |
a
h/m/bAM, human/mice/bovine alveolar macrophage; me, methylation; ac, acetylation; qRT-PCR, quantitative reverse trancsription-PCR; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-associated cell sorting; RRB-seq, reduced-representation bisulfite sequencing; NA, not applicable.
ADVANCES IN EPIGENETICS OF ALVEOLAR MACROPHAGES IN TUBERCULOSIS
The transcriptome of alveolar macrophages is altered by M. tuberculosis infection.
Dysregulated gene expression in AM is the result of epigenetic modifications induced by M. tuberculosis infection. Murine and bovine models have been particularly informative in this regard due to the feasibility of acquiring primary lung lavages and tissue. Significant changes to metabolism, defective apoptosis, macrophage polarization, and host-detrimental inflammation are common themes in dysregulated AM during M. tuberculosis infection. Gene expression studies of M. tuberculosis-infected AM validate that the epigenotypes of these cells do indeed predispose them with impaired capabilities to clear pathogens. Specifically, multiple studies have observed the induction of type I interferon (IFN) responses in AM infected with M. tuberculosis (Fig. 2). Type I IFNs are well established to be host detrimental in the context of TB, as they trigger an immune response that ultimately drives host pathology (70–72). Ex vivo infection of AM from healthy donors compared to TB patients demonstrated the impaired immune response of AM in TB (73). AM from healthy donors expressed genes enriched in IFN-γ responses, including IFNGR2, CXCL1, CXCL5, GBP2, HCK, and KYNU. In contrast, AM from TB patients expressed genes enriched in type I IFN responses, including IRF1, IFIT2, IFIT3, CXCL9, MX1, HELZ2, EPSTI1, CSRNP1, and SOCS1 (73) (Table 1). Upregulation of the RIG-I-like receptor genes, which lead to activation of IRF transcription factors and the production of type I IFNs, is also observed in ex vivo infection of bAM with M. bovis (67). In addition, several key genes in apoptosis and lysosomal pathways were dysregulated in infected bAM (Table 1). In mice, M. tuberculosis induced upregulation of type I IFNs in AM, which impaired glycolytic metabolism and induced mitochondrial stress (Fig. 2) (74). Glycolysis and mitochondrial function were rescued in AM from IFNAR−/− mice during pulmonary M. tuberculosis infection, demonstrating the function of this pathway in vivo (74).
FIG 2
Lipid metabolism is another key immune response that is impaired during M. tuberculosis infection of AM. Dual host-microbe transcriptome sequencing (RNA-seq) of M. tuberculosis-infected AM showed that M. tuberculosis thrived in AM because of an increase in intracellular lipid and iron availability, which also promoted foamy macrophage proliferation (65). Compared to healthy individuals, AM from pulmonary TB patients have significantly downregulated CES1, a gene that mediates the breakdown of cholesterol, which would result in increased availability of cholesterol for M. tuberculosis replication (75). Genes that were upregulated in AM from TB patients also include tissue-damaging MMP proteins and genes that negatively regulate phagocytosis (Table 1). Different from M. tuberculosis infection, murine AM infected with M. bovis BCG are successfully able to reduce intracellular cholesterol by downregulating ABC transporters and ACAT1, ultimately promoting host-beneficial autophagy (76). In human AM, autophagy is enhanced by upregulation of NOD2, as determined by ex vivo infection of AM with M. tuberculosis (77). This highlights that cholesterol metabolism is an attractive candidate for host-directed therapy, the difference in pathogenicity between M. tuberculosis and M. bovis BCG, and the potential differences between murine and human TB models.
Recently, several studies have determined that a major explanation for why AM are more permissive to M. tuberculosis is due to a significant delay in the initiation of an antibacterial immune response compared to infected MDM from the same models. M. tuberculosis infection of AM from healthy human subjects triggered the upregulation of select genes at the onset of infection, but a robust immune response lagged until 3 days postinfection (Table 1) (66). Furthermore, an in vivo murine model comparing infected and uninfected AM from the same animal detailed that the TF NRF2 induces a cell-protective state, which inadvertently allows M. tuberculosis time to replicate before an inflammatory response is initiated (18). Papp et al. show that the gene set that was upregulated following ex vivo infection of AM (and MDM) was enriched in IL-10 pathways, suggesting that an anti-inflammatory response was induced, which was consistent with lower levels of NOD2 and increased expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) (66) (Table 1). Interestingly, downregulation of IL-10 is a correlate of protection in M. tuberculosis-infected PPARγ knockout mice, as these mice showed increased resistance to M. tuberculosis infection (78). PPARγ is a major regulator of AM development, and accordingly also regulates GM-CSF production (78). The delayed immune response and increase in anti-inflammatory pathways observed in AM may also be due to an overall shift to an M2 phenotype. During M. bovis infection, there is a strong enrichment for M2-associated genes in concordance with increased levels of IL-10 and expression of genes that negatively regulate apoptosis and lysosomal function (67) (Table 1). Similarly, impaired lysosomal maturation, as well as unchecked inflammatory neutrophil infiltration, is present in AM from human infants, for whom M. tuberculosis infection is highly pathogenic (79). Collectively, reports using AM from human, bovine, and mouse models have demonstrated that the gene expression program of AM during M. tuberculosis infection is highly dysregulated. Accordingly, the genome-wide changes in epigenetic regulation and its associated mechanisms in alveolar macrophages are of critical importance to understanding the underlying immune dysregulation in TB.
DNA methylation contributes to changes in the epigenome of M. tuberculosis-infected alveolar macrophages.
Genome-wide methylation profiles of THP-1 monocytes and human MDM have established that M. tuberculosis infection dysregulates host gene expression through mechanisms dependent on modifications in DNA methylation. DNA methylation profiles of peripheral blood mononuclear cells (PBMC) from TB patients have also revealed that DNA methylation signatures may regulate certain immune responses in vivo. Indeed, global methylation analysis of PBMC from TB patients revealed over 1,000 differentially methylated regions compared to healthy controls and almost 4,000 differentially methylated regions following completion of treatment, with most of the affected genes being linked to the autophagy pathway (25). In addition, several regions of the TLR2 promoter were methylated in PBMC from TB patients, resulting in decreased TLR2 expression, although the production of TNF-α and IFN-γ increased in the serum of these patients (80). The gene encoding the vitamin D receptor (VDR) was also differentially methylated, leading to decreased expression of members of the AKT signaling pathway, a known signaling cascade triggered by the VDR (81). Genome-wide methylation changes were not restricted to virulent M. tuberculosis, as PBMCs from BCG-vaccinated individuals also showed distinct immunoprotective methylation signatures when challenged with M. tuberculosis ex vivo (82).
Recent studies have begun to uncover the role of DNA methylation in AM during M. tuberculosis infection. In a prospective study, AM from healthy individuals who developed latent TB infection displayed a distinct methylation profile compared to individuals who remained healthy throughout the study (83). Here, pathways that were enriched in differentially methylated regions included components of the pentose phosphate pathway and Ras signaling pathway (Fig. 2). Informatively, the methylation signature was observed in samples collected at the start of the study, while subjects were IFN-γ release assay (IGRA) negative. This observation indicates that AM in certain individuals are either epigenetically predisposed to have an impaired immune response to M. tuberculosis or that DNA methylation is targeted prior to inducing the adaptive immune response (i.e., positive IGRA test) (83). Either way, the discovery of this signature will have value as a predictor of latent TB. The same group conducted a related study that supported the latter hypothesis, which was published recently as a preprint. In this study, the DNA methylation profiles of AM from individuals who had been in contact with TB patients were evaluated. Distinct methylation signatures were identified in people who were exposed to active TB patients but remained IGRA negative (84). These methylation signatures matched the signatures from active and latent TB patients from the same study. The pathways enriched in these signatures varied slightly from the earlier study, as top-scoring pathways were HIF1-α, vitamin D metabolism, WNT, and p38 signaling pathways (Fig. 2 and Table 1). These signatures corroborate reports that HIF1-α coordinates a metabolic shift to glycolysis to promote IFN-γ-dependent host immunity against TB (85). Intriguingly, there were more differentially methylated regions in AM than PMBCs from the same individuals, as such regions in PBMCs were enriched in IFN-γ pathways whereas AM were not. In a separate study, PBMC from BCG responders displayed differential methylation of several gene promoters, including IFN-γ, RASAL1, TLR6, and NFKBIE, for up to 4 months as well as enhanced antimycobacterial activity of MDM in ex vivo assays (86). This parallel suggests that certain DNA methylation mechanisms that are induced upon exposure to M. tuberculosis, at least in the initial stages of infection, are host-protective responses. In contrast to changes in the DNA methylation profile in M. tuberculosis-infected human AM, DNA methylation patterns remain largely unchanged during M. bovis infection of bAM. Instead, M. bovis induces intermediate methylation of several immune loci, which was hypothesized to indicate that differential methylation is time and context dependent in this infection model (87). Elucidation of the methylation signatures that are induced in lung immune cells during TB is a clinically important and emerging field. Further studies that aim to link the antibacterial and immunoevasion mechanisms that are mediated through changes to the DNA methylome may be a way to identify novel targets for TB host-directed therapy.
M. tuberculosis induces chromatin structure remodeling in alveolar macrophages.
There is substantial evidence from THP-1 and MDM models that M. tuberculosis induces changes to host chromatin structure to dysregulate the immune response (23, 24, 26, 29–31, 33–36, 88). Like DNA methylation, global histone acetylation and methylation patterns are present in PBMCs from TB patients (25). Signatures for H3K14ac and H3K27me2, which mark active and repressed genes, were correlated with decreased 1-year survival rates for TB patients (25). These histone marks were determined to be mediated by HDAC1 and KDM6B and resulted in changes to levels of TNF-α, IFN-γ, and IL-1β in TB patients compared to healthy controls (Fig. 2). Recently, genome-wide changes to chromatin accessibility in human AM infected with M. tuberculosis ex vivo were analyzed using ATAC-seq and H3K27ac profiling to identify regions of active transcription. Significant changes to chromatin accessibility were identified in M. tuberculosis-infected AM, as approximately twice as many regions gained accessibility compared to regions that showed reduced accessibility (89). Chromatin accessibility signatures were enriched in the promoters of NF-κB, TNF-α, and type I IFN signaling pathways and were correlated with a concomitant increase of H3K27ac at the promoters of CXCL10, IFI44L, APOBEC3A, and MX1 (Fig. 2 and Table 1). Parallel transcriptomics results were also enriched in NF-κB, type I IFN signaling, and NLR signaling. From the same study, TF motif enrichment analysis revealed that chromatin regions that gained accessibility were enriched in type I IFN-regulatory factors, including IRF9 and ZNF684, which have emerged as a key target of epigenetic regulation during M. tuberculosis infection (Fig. 2) (89). Even though M. bovis-infected bAM display only moderate changes to the DNA methylome, their transcriptomes highlight several chromatin-modifying enzymes (Table 1) (87). Genome-wide profiling for specific histone modifications in bAM infected with M. bovis have also produced parallels for human models. Bovine AM were profiled using chromatin immunoprecipitation sequencing (ChIP-seq) for H3K4me3 and H3K27me3, which are markers of gene expression activation or repression, respectively, and RNA polymerase II. In concordance with the transcriptomic changes previously discussed in infected bAM, active promoters in infected bAM were enriched at RIG-I pathways as well as phosphatidylinositol 3-kinase (PI3K)/AKT pathways (29, 67) (Fig. 2 and Table 1). This result is consistent with a previous report that linked small nucleotide polymorphisms (SNPs) in the bovine PI3K/AKT pathway to resistance against M. bovis infection (87). In addition, this study showed increased gene activity with H3K4me3 marks at ARG2 and BCL2A1 in bAM (Fig. 2), which promotes an M2 macrophage phenotype and negatively regulates apoptosis, respectively (29).
Given the massive changes in chromatin architecture during M. tuberculosis infection, two separate studies have evaluated the effects of histone deacetylase (HDAC) inhibitors on AM infected with M. tuberculosis. HDAC inhibitors are widely used to treat cancer and other chronic diseases and, more recently, has gained traction as novel host-directed therapy for TB (6, 90, 91). Treatment with the pan-HDAC inhibitor suberanilohydroxamic acid (SAHA/vorinostat) enhanced the immune response of AM infected with M. tuberculosis, as indicated by increased production of IL-1β and decreased levels of IL-10 as well as a shift to glycolytic metabolism (92) (Fig. 2). This study suggests that regulation of IL-1β and IL-10 is mediated at the histone level in M. tuberculosis infection and that modulating histone modifications using HDAC inhibitors may have clinical applications. Out of a panel of specific HDAC inhibitors, inhibition of HDAC3 with RGFP9966 showed the strongest antibacterial effect on M. tuberculosis-infected AM (30). Although only limited to a few reports, these collective studies using AM have confirmed that M. tuberculosis infection induces modifications in chromatin structure that lead to large-scale transcriptional changes that govern the efficacy of the immune response to M. tuberculosis infection.
Alveolar macrophages are reprogrammed by trained immunity.
The underlying concept of trained immunity is intimately linked to the epigenetic modifications that are incurred following infection. Trained immunity is the result of epigenetic reprogramming of cells following a vaccine or other stimulus that leads to an enhanced immune response upon reinfection (93–96). It has been established that BCG vaccination induces trained immunity as a protective mechanism against nonspecific infections and can induce strong protective efficacy against TB when administered by the intravenous route (97–99). PBMCs from BCG-vaccinated individuals produce a more robust immune response upon challenge with M. tuberculosis in vitro, as characterized by increased expression of TNF-α, IL-6, and TLR4. Enhanced expression of these genes is mediated by epigenetic changes at their respective promoters through a mechanism dependent on increased H3K4me3 and increased NOD2 signaling (100). This is recapitulated in mice vaccinated with BCG via the intravenous route, where genes associated with H3K27ac or H3K4me3 in bone marrow-derived macrophages were enriched in host-protective TB pathways even before infection (101). However, in the same study, ATAC-seq revealed that chromatin regions that gained accessibility were enriched in genes of the type I IFN regulatory pathways (IRF2, IRF7, IRF9, STAT1, and STAT2) (101), which was unexpected given that the type I IFN response is typically associated with host-detrimental responses in TB (70–72). This shows the complex nature of the IFN response in TB and may also indicate differences between mice and humans. There is also compelling evidence that BCG vaccination induces trained immunity in neutrophils through epigenetic reprogramming of these cells into a more activated, inflammatory cell type that has increased ability to clear M. tuberculosis (102). Here, H3K4me3 was enriched at STAT4, IL-8, IL-1β, mTOR, and PFKP, and remarkably, these changes were observed to last up to 3 months.
While the major landmark studies described above relied on PBMC, recent work sought to assess whether trained immunity occurs in AM. Evaluations on the effect of intradermal BCG in human AM obtained before and after vaccination did not show evidence of trained immunity (86, 103). In these studies, AM obtained through induced sputum at 2 weeks and 3 months postvaccination displayed reduced expression of CD11b and MHC-II and no change in select inflammatory cytokines (86, 103). The reasons for these negative findings are now clear, as multiple studies have shown that the route of BCG administration plays a critical role in the resulting protective immune response (97, 99, 101). Indeed, AM from mice administered with BCG intranasally (pulmonary vaccination) displayed the characteristic markers of activation, including CD86, MHC-II, and inducible nitric oxide synthase (iNOS) (104–107) (Fig. 3 and Table 1). This corresponded to an upregulation of proinflammatory genes, including Nos2, Ifng, Irf8, and Ccl2, and genes involved in metabolism, such as Hk2, Ldlr, G6pdx, and Ldha (Fig. 3) (Table 1) (107). After ex vivo infection with M. tuberculosis, “trained” AM were able to prevent the dissemination of M. tuberculosis to other immune cells in the lung. Proliferation of trained AM was also observed, and this led to a lasting effect of up to 7 months of enhanced activation and antimycobacterial responses (107). Trained immunity in AM has also been demonstrated through respiratory mucosal delivery of an adenovirus-vectored (Ad-TB) TB vaccine. In this case, AM from Ad-TB vaccinated mice contained M. tuberculosis infection much more effectively than unvaccinated controls and maintained an activated phenotype and glycolytic metabolism (108) (Fig. 3). Importantly, the enhanced immune response was generated exclusively by tissue-resident AM (108). In a third example demonstrating trained immunity in AM, the contained M. tuberculosis infection model was used to determine that preexposure to a low dose of M. tuberculosis conferred protection to subsequent infection (109). The gene expression profiles of AM from mice preexposed to M. tuberculosis were substantially different following reexposure to M. tuberculosis and were characterized by IFN-γ and IFN-α pathways. Of particular interest in this study is the conclusion that the changes to gene expression that were observed did not correlate with any changes to chromatin accessibility but were reported to be a result of sustained, low-grade IFN-γ signaling (109). Interestingly, BCG-induced trained immunity was also demonstrated to play a key role in circulating neutrophils (110). In fact, protection from M. tuberculosis challenge was maintained even when macrophages were depleted and occurred exclusively in the first 7 days of infection. In contrast, another study showed that while neutrophils were activated by BCG, they were not by themselves responsible for a robust immune response (111). Collectively, there is emerging evidence that a protective, trained immune response can be induced in AM and circulating neutrophils. However, there are no studies, to our knowledge, that have examined the existence of trained immunity in either human lung neutrophils or human AM in the context of TB. Moving forward, this should be a priority for the field of trained immunity in TB.
FIG 3
CLINICAL POTENTIAL OF TARGETING EPIGENETIC MECHANISMS FOR TUBERCULOSIS
Targeting epigenetic mechanisms represents a promising strategy for novel, adjunctive therapy for TB. While there remains much to unravel given that we have just begun to elucidate the host epigenetic responses to M. tuberculosis infection using lung immune cells, drugs that target epigenetic modifications (“epidrugs”) already exist and are routinely used to treat other diseases. The most significant use of epidrugs is to treat various forms of cancer, and there are also several chronic illnesses that benefit from their use, such as arthritis, diabetes, and graft versus host disease (6, 90, 91). Use of epidrugs has also been extensively explored in the context of other infectious diseases, the best examples of which are the use of HDAC inhibitors to treat HIV (112–115). Treatment of other viral infections with latent phases, such as hepatitis B, HSV-1, EBV, and HCMV, with epigenetic therapies is also in practice (116).
While there are currently no clinical examples of targeting epigenetic mechanisms for TB treatment, several animal and preclinical models provide evidence that certain epidrugs have antimycobacterial effects. Thus far, these models focus on the use of HDAC inhibitors or activators, which is in line with efforts to repurpose drugs that are already approved to treat other diseases. Modulating the activity of SIRTs, a class of HDAC proteins, is a strategy that has shown success for TB host-directed therapy. Using resveratrol or SRT1720 to activate SIRT1 significantly enhanced the immune response to M. tuberculosis infection in mice and was found specifically to modulate the inflammatory response in lung monocytes (88). Targeting of SIRT2 with AGK2 in T cells led to an enhanced adaptive immune response to TB through enhanced antigen presentation in IFN-γ and IL-17 pathways (117). Inhibition of SIRT2 also enhanced the immune response of macrophages through H3K18 deacetylation (117). Like SIRT1, SIRT3 is downregulated upon M. tuberculosis infection with host-detrimental effects (33, 35). Activation of SIRT3 with HKL improved the antibacterial response in macrophages through enhanced autophagy, phagolysosome fusion, and reduced mitochondrial damage (33, 35).
Treatment with pan-HDAC and HDAC3 inhibitors has also shown host-beneficial outcomes in AM and zebrafish models; furthermore, treatment with inhibitors to HDAC1 and HDACIIa has shown therapeutic potential in vitro (30, 92, 118). Inhibition of HDACIIa in zebrafish with TMP195 or TMP269 enhanced antibacterial effects primarily in M2 macrophages, suggesting that this may also be effective in AM that possess M2 characteristics (118). However, inhibition of HDAC1 with MS-275 led to host-detrimental effects due to upregulation of tissue-damaging MMP-1, whereas inhibition of histone acetyltransferases with HATi II downregulated MMP-1 and MMP-3 (34). Together, these results demonstrate the complexity of modulating epigenetic mechanisms globally in a disease state (34). Interestingly, differential transcriptional regulation of HDACs is also a factor in individuals who are resistant to TB (119). In summary, there is substantial evidence that targeting epigenetic mechanisms that are dysregulated in M. tuberculosis infection can have host-beneficial effects. The translation of these findings from bench to bedside will require additional research using clinically relevant cell models, in vivo models, and clinical trials.
CONCLUDING REMARKS
The field of host epigenomics in TB has made remarkable progress and defined TB as an infectious disease that dysregulates host epigenetic machinery. Elucidating these complex mechanisms has been feasible largely through studies using in vitro small-animal and human MDM models. Importantly, recent advances have expanded to include the use of primary lung immune cell models. Studies using AM emulate many findings from MDM models, but they also reveal new aspects of the host response. These unique findings stem from phenotypic and epigenetic differences between these cells at both steady state and during the immune response to infection. It is also important to recognize that macrophages possess incredible functional and phenotypic heterogeneity even within a specific classification, such as AM or MDM (49, 64, 65, 120). While this review uses the general classification of AM and MDM, this is a simplification of the dynamic physiological environment, where there likely exists more nuanced population heterogeneity in the macrophage compartment, particularly in the TB granuloma (121, 122). Indeed, in addition to subpopulations of AM and MDM, macrophage populations found within the TB granuloma are incredibly diverse, including epithelioid histiocytes, multinucleated giant cells, and foamy macrophages (121–126).
Advances in epigenomics of lung immune cells in TB have identified specific gene expression changes, mediated by TF, DNA methylation, chromatin structure, and trained immunity, that reflect both M. tuberculosis immunoevasion strategies and the host antibacterial response (Fig. 2 and 3; Table 1). In fact, many of these changes are in pathways that are more relevant in AM than MDM, such as lipid metabolism and delayed immune response. The field is still limited, though, by a lack of genome-wide studies, including chromatin accessibility of AM from TB patients. The feasibility of conducting such studies is higher than ever as novel omics methods require fewer cells and become increasingly accessible. It would also be prudent to use epigenomic data to identify specific and druggable host protein targets for host-directed therapy, which will mitigate the global and off-target effects of drugs like HDAC inhibitors or activators. The outlook for novel adjunctive therapy to supplement existing TB vaccination and antibiotics is promising and will be imperative to combat the world’s deadliest bacterial pathogen.
ACKNOWLEDGMENTS
We thank members of the Sun laboratory for helpful discussions. We apologize to all the investigators whose work we were unable to cite and discuss due to space limitations.
This work was supported by grants from the Canadian Institutes of Health Research (CIHR) PJT-162424 and the National Sanitarium Association Scholar’s Program to J.S. and the University of Ottawa Faculty of Medicine Translational Research Grant to J.S. and G.G.A. K.M. was supported by a graduate scholarship from the University of Ottawa Centre for Infection, Immunity, and Inflammation. Y.C.L. was supported by a Canada Graduate Scholarship (CIHR-MSc) and the Ontario Graduate Scholarship. N.R. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) PGS-Doctoral Scholarship.
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Author Bios
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
Katrina Madden is a 3rd year Ph.D. candidate in the Department of Biochemistry, Microbiology, and Immunology at the University of Ottawa. She was born in Parry Sound, Ontario, and completed her undergraduate degree in Biomedical Sciences at the University of Waterloo. After two years of working in industry, she completed her M.Sc. degree in Immunology and Global Health at Maynooth University in Ireland. Following her Masters, Katie worked at Western University as a research/technical assistant with the HIV investigators group and the Imaging Pathogens for Knowledge Translation (ImPaKT) facility. Her current research interests include epigenetic regulation in tuberculosis, specifically in primary lung immune cells. This research will define novel drug targets for adjunctive TB therapies and further elucidate host biology in tuberculosis.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
Yi Chu Liang is a Ph.D. student in the Microbiology and Immunology program at the University of Ottawa. He is interested in the development of novel host-directed therapeutics for the treatment of tuberculosis. In particular, he is working on the development of inhibitors against host phosphatases that are hijacked by Mycobacterium tuberculosis to promote infection. He completed a B.Sc. in Biochemistry at the University of Ottawa in 2019.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
Nusrah Rajabalee received her Bachelors degree in Biomedical Sciences in 2018 from the University of Ottawa. She subsequently enrolled in the Microbiology and Immunology graduate program at the University of Ottawa as a Ph.D. student. Nusrah’s principal research interest is to investigate the role of host transcription factors during Mycobacterium tuberculosis infection. The knowledge obtained from her research will significantly improve the current understanding of the molecular mechanisms underlying the host macrophage response against M. tuberculosis and simultaneously reveal novel targets for host-directed therapy of tuberculosis.
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
School of Public Health, University of Ottawa, Ottawa, Ontario, Canada
Division of Respirology, Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada
Gonzalo G. Alvarez is an Associate Professor of Medicine in the Faculty of Medicine at the University of Ottawa and the Head of Respirology at The Ottawa Hospital. He is a Scientist at the Ottawa Hospital Research Institute. He obtained his degree in Internal Medicine at the University of Ottawa and his fellowship in Respiratory Medicine at the University of British Columbia and then went on to Harvard University to complete his Masters of Public Health. He is the director of the Taima TB set of projects in Nunavut, Canada, which is a group aimed at helping Inuit in Canada stop the transmission of TB in their communities (https://taimatb.tunngavik.com/). He holds a research chair in tuberculosis in Indigenous northern communities at the University of Ottawa. He is the Nunavut respirology consultant for pulmonary health and TB.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Ontario, Canada
Jim Sun is an Assistant Professor in the Department of Biochemistry, Microbiology, and Immunology at the University of Ottawa. He obtained his Ph.D. from the University of British Columbia in 2012, where he made significant contributions to the field of phagosome biogenesis and host-pathogen interactions between the macrophage and Mycobacterium tuberculosis. He then completed a postdoctoral fellowship at the University of Alabama at Birmingham, where he contributed to the discovery and characterization of a novel protein toxin produced by M. tuberculosis. Since starting his own research lab at the University of Ottawa in 2017, he has continued his dedication to tuberculosis research. His research program focuses on identifying and understanding novel host signaling pathways and epigenetic mechanisms exploited by M. tuberculosis to persist within macrophages. The discovery and characterization of these pathways and mechanisms will be instrumental for advancing novel and alternative host-directed therapies to treat tuberculosis.
Information & Contributors
Information
Published In
Infection and Immunity
Volume 90 • Number 5 • 19 May 2022
eLocator: e00522-21
Editor: Anthony R. Richardson, University of Pittsburgh
PubMed: 35311579
Copyright
© 2022 American Society for Microbiology. All Rights Reserved.
History
Published online: 21 March 2022
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Anthony R. Richardson
Editor
University of Pittsburgh
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