Alveolar macrophages from persons living with HIV show impaired epigenetic response to Mycobacterium tuberculosis

Correa-Macedo, Wilian; Fava, Vinicius M.; Orlova, Marianna; Cassart, Pauline; Olivenstein, Ron; Sanz, Joaquín; Yong, Xu; Dumaine, Anne; Sindeaux, Renata H.M.; Yotova, Vania; Pacis, Alain; Girouard, Josée; Kalsdorf, Barbara; Lange, Christoph; Routy, Jean‐Pierre; Barreiro, Luis B.; Schurr, Erwin

doi:10.1172/jci148013

Cited by 22 publications

(22 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This may be due to the phenotypic and functional differences between hAM and THP-1 cells, conditions of Mtb infection (MOI, time, strain), or variability between patient samples caused by increased genomic heterogeneity. Interestingly, the DAR that Correa-Macedo et al reported are annotated to many of the same genes that the DAR in our analysis annotated to ( RSAD2, MX1,2, IFIT1,2,3 , and IFITM3 ) Pathway analysis by Correa-Macedo et al also demonstrated enrichment of type I IFN signalling pathways, while IRF9 and ZNF685 motifs, which are involved with type I IFN signaling responses, were significantly enriched in TFBM analysis (Correa-Macedo et al . 2021).…”

Section: Discussionsupporting

confidence: 70%

“…The only previous report to investigate global CA patterns upon Mtb infection was a report by Correa-Macedo et al where the authors investigated CA and gene expression patterns of primary human alveolar macrophages (hAM) infected with Mtb ex vivo (Correa-Macedo et al . 2021).…”

Section: Discussionmentioning

confidence: 99%

“…The limitation of these studies is that ChIP-seq analyzes specific changes to nucleosome structure and does not simultaneously capture genome-wide changes to chromatin accessibility. 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).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Madden

Hamra

Berton

et al. 2022

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Madden

Hamra

Berton

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Similar to BC, HAART has adverse effects on other lung cells. Recent study revealed that alveolar macrophages from HIV − individuals receiving PrEP demonstrated an impaired epigenetic and transcriptional responsiveness to Mycobacterim tuberculosis 99 . Of interest, HAART also causes suppressive impact on microbiota diversity in the gut, which potentially causes intestinal dysbiosis and incompletely restore gut mucosal barrier dysfunction in patients 100 – 103 .…”

Section: Discussionmentioning

confidence: 99%

Impaired differentiation of small airway basal stem/progenitor cells in people living with HIV

Chung

Khan

Andreoli

et al. 2022

Sci Rep

View full text Add to dashboard Cite

With highly active anti-retroviral therapy (HAART), higher incidence of airway abnormalities is common in the HIV population consistent with the concept of accelerated lung “aging”. Our previous findings demonstrated that HIV induces human airway basal cells (BC) into destructive and inflammatory phenotypes. Since BC function as stem/progenitor cells of the small airway epithelium (SAE), responsible for self-renewal and differentiation of SAE, we hypothesized that BC from people living with HIV (PLWH) may have altered differentiation capacity that contribute to premature aging. The data demonstrates that BC from PLWH have impaired capacity to differentiate in vitro and senescent phenotypes including shortened telomeres, increased expression of β-galactosidase and cell cycle inhibitors, and mitochondrial dysfunction. In vitro studies demonstrated that BC senescence is partly due to adverse effects of HAART on BC. These findings provide an explanation for higher incidence of airway dysfunction and accelerated lung aging observed in PLWH.

show abstract

“…Notably, AMs from HIV+ and HIV- PrEP study groups both had a weaker transcriptional response when challenged with Mtb compared to AMs from healthy controls. Furthermore, AMs from HIV- PrEP and HIV+ donors showed no change in chromatin state upon challenge, unlike AMs from healthy controls which displayed a significant change in chromatin accessibility ( 121 ). Collectively, these findings suggest that although ART greatly improves the quality of life of PLWH and does restore many of their immune parameters it does not come without side effects.…”

Section: Pulmonary Immune Dysregulation During Hiv Infectionmentioning

confidence: 99%

Pulmonary Immune Dysregulation and Viral Persistence During HIV Infection

2022

View full text Add to dashboard Cite

Despite the success of antiretroviral therapy (ART), people living with HIV continue to suffer from high burdens of respiratory infections, lung cancers and chronic lung disease at a higher rate than the general population. The lung mucosa, a previously neglected HIV reservoir site, is of particular importance in this phenomenon. Because ART does not eliminate the virus, residual levels of HIV that remain in deep tissues lead to chronic immune activation and pulmonary inflammatory pathologies. In turn, continuous pulmonary and systemic inflammation cause immune cell exhaustion and pulmonary immune dysregulation, creating a pro-inflammatory environment ideal for HIV reservoir persistence. Moreover, smoking, gut and lung dysbiosis and co-infections further fuel the vicious cycle of residual viral replication which, in turn, contributes to inflammation and immune cell proliferation, further maintaining the HIV reservoir. Herein, we discuss the recent evidence supporting the notion that the lungs serve as an HIV viral reservoir. We will explore how smoking, changes in the microbiome, and common co-infections seen in PLWH contribute to HIV persistence, pulmonary immune dysregulation, and high rates of infectious and non-infectious lung disease among these individuals.

show abstract

Alveolar macrophages from persons living with HIV show impaired epigenetic response to Mycobacterium tuberculosis

Cited by 22 publications

References 55 publications

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

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

Impaired differentiation of small airway basal stem/progenitor cells in people living with HIV

Pulmonary Immune Dysregulation and Viral Persistence During HIV Infection

Contact Info

Product

Resources

About