Surveying the Epigenetic Landscape of Tuberculosis in Alveolar Macrophages

Madden, Katrina; Liang, Yi Chu; Rajabalee, Nusrah; Alvarez, Gonzalo G.; Sun, Jim

doi:10.1128/iai.00522-21

Cited by 9 publications

(7 citation statements)

References 121 publications

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“…Further analysis of the 3D structure of DNA could be investigated using HiChIP. It is also important to note that this study was conducted exclusively with THP-1 macrophages, and while many identified signatures were consistent with literature from primary human monocyte derived macrophages, it would be prudent to confirm key findings in primary human macrophages, including alveolar macrophages, which are the most clinically relevant model for Mtb infection (Madden et al . 2022).…”

Section: Discussionsupporting

confidence: 72%

“…The only previous report to investigate global chromatin accessibility patterns in macrophages upon Mtb infection was a report by Correa-Macedo et al conducted in the context of HIV co-infection, which did not focus in-depth on the effects of Mtb infection alone (Correa-Macedo et al 2021). In contrast, numerous studies have examined the impact of Mtb infection on the transcriptome of macrophages (Madden et al 2022). These studies have shown a host-detrimental type I interferon (IFN) signature in Mtb infected cells and TB patients (Moreira-Teixeira et al 2018).…”

Section: Introductionmentioning

confidence: 99%

“…2021). In contrast, numerous studies have examined the impact of Mtb infection on the transcriptome of macrophages (Madden et al . 2022).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Madden

Hamra

Berton

et al. 2022

Preprint

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Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. The success of Mtb as a human pathogen depends on its ability to manipulate host immune response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, may play a role in the regulation of chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Using combinatorial chromatin accessibility (ATAC-seq) and transcriptomics (RNA-seq) profiling of wild-type (WT), PPM1A knockout (ΔPPM1A) and PPM1A overexpressing (PPM1A+) macrophages, we demonstrate that Mtb infection induces global chromatin remodeling consistent with changes in gene expression signatures. The strongest concordant chromatin accessibility and gene expression signature triggered by Mtb infection was enriched for genes involved in the type I interferon (IFN) signaling pathways. Modulation of PPM1A expression results in altered chromatin accessibility signatures during Mtb infection that are reflected in the total number, chromosome location and directionality of change. Transcription factor motif analysis revealed an enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including IRF4, MEF2A, CEBPD and JDP2. In contrast, both deletion and overexpression of PPM1A produced unique transcription factor enrichment signatures linked to the genomic regions with altered chromatin accessibility. Our study demonstrates that altered type I IFN responses in Mtb-infected macrophages occurs as a result of genome-wide changes in chromatin accessibility, and that PPM1A likely plays a role in a subset of these signatures.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Madden

Hamra

Berton

et al. 2022

Preprint

Self Cite

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“…Similarly, a distinct DNA methylation profile, which was enriched in the pentose phosphate pathway, T cell migration and IFN‐γ production pathways, was uncovered in alveolar macrophages (AMs) after M. tuberculosis infection [39]. Intriguingly, there were more differentially methylated regions in AMs than in PMBCs within the same individual [38]. In addition, altered DNA methylation pattern associated with the immune gene loci can also be detected in the sperm DNA of parental male mice infected with fungus C. albicans [40].…”

Section: Trained Immunity (Innate Immunological Memory)mentioning

confidence: 99%

“…Additionally, gene ontology analysis revealed that promoters with altered DNA methylation patterns were strongly enriched among immune-related genes, thereby enhancing the resistance of macrophages to mycobacteria [35,36]. Indeed, a global methylation analysis showed that there existed over 1000 differentially methylated regions between PBMCs of tuberculosis (TB) patients and healthy controls, and there were still almost 4000 differentially methylated regions following completion of anti-TB treatment, and the majority of the affected genes were associated with the autophagy pathway [37,38]. Similarly, a distinct DNA methylation profile, which was enriched in the pentose phosphate pathway, T cell migration and IFN-γ production pathways, was uncovered in alveolar macrophages (AMs) after M. tuberculosis infection [39].…”

Section: Epigenetic Reprogrammingmentioning

confidence: 99%

Macrophage memory: Types, mechanisms, and its role in health and disease

Fang,

Li,

Liu

et al. 2023

Immunology

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On the basis of the mechanisms of action and characteristics of immune effects, immunity is commonly categorized into innate and adaptive immunity. Adaptive immunity is associated with the response to non‐self‐entities and is characterized by high specificity and memory properties. In contrast, innate immunity has traditionally been considered devoid of memory characteristics. However, an increasing number of studies have sought to challenge this conventional immunological dogma and shown that innate immune cells exhibit a more robust and rapid response to secondary stimulation, thus providing evidence of the immunological memory in innate immunity. Macrophages, which are among the most important innate immune cells, can also acquire memory phenotype that facilitates the mediation of recall responses. Macrophage memory is a relatively new concept that is revolutionizing our understanding of macrophage biology and immunological memory and could lead to a new class of vaccines and immunotherapies. In this review, we describe the characteristics and mechanisms of macrophage memory, as well as its essential roles in various diseases.

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