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Alveolar macrophages from persons living with HIV show impaired epigenetic response to Mycobacterium tuberculosis
Wilian Correa-Macedo, … , Luis B. Barreiro, Erwin Schurr
Wilian Correa-Macedo, … , Luis B. Barreiro, Erwin Schurr
Published September 2, 2021
Citation Information: J Clin Invest. 2021;131(22):e148013. https://doi.org/10.1172/JCI148013.
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Research Article AIDS/HIV Infectious disease

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

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Abstract

Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (M. tuberculosis) followed by rapid progression to disease. Alveolar macrophages (AMs) are the first cells of the innate immune system that engage M. tuberculosis, but how HIV and antiretroviral therapy (ART) affect the anti-mycobacterial response of AMs is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AMs to M. tuberculosis, we obtained AMs by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as preexposure prophylaxis (PrEP) to prevent HIV infection. Following in vitro challenge with M. tuberculosis, AMs from each group displayed overlapping but distinct profiles of significantly up- and downregulated genes in response to M. tuberculosis. Comparatively, AMs isolated from both PLWH and PrEP subjects presented a substantially weaker transcriptional response. In addition, AMs from HC subjects challenged with M. tuberculosis responded with pronounced chromatin accessibility changes while AMs obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state. Collectively, these results revealed a stronger adverse effect of ART than HIV on the epigenetic landscape and transcriptional responsiveness of AMs.

Authors

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

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Figure 3

AM chromatin remodeling in response to M. tuberculosis.

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AM chromatin remodeling in response to M. tuberculosis.
 (A) Significanc...
(A) Significance of chromatin changes is plotted against the magnitude of the change. Significantly open or closed chromatin regions at a FDR of 5% are represented by red or blue dots, respectively. Counts of DOC regions are given at the top. Vertical dashed lines indicate the minimum log2FC of 0.2 on the x axis. For HC subjects, 23.3% of the tested regions displayed significant chromatin remodelling in response to M. tuberculosis, whereas PLWH and PrEP subjects lacked significant chromatin changes. The raw P value significance cut-off for FDR less than 5% varies as the FDR procedure is based on the P value distributions that are intrinsic to each tested group. (B) Density of the absolute log2FC for 12,360 DOC regions is shown for HC, PrEP, and PLWH groups in blue, green, and red, respectively. Mean log2FC for each group is highlighted by horizontal lines. PrEP and PLWH groups showed strongly impaired chromatin remodelling in response to M. tuberculosis compared with the HC group. (C) Pathway/GO term enrichment analysis of genes assigned to DOC regions for the HC response to M. tuberculosis. GO biological process (BP), KEGG, and Reactome pathways to which at least 5 genes had been assigned are plotted against the negative log10 FDR. In total, 724 of the 8066 tested terms were significant. Enrichment analysis indicated that M. tuberculosis challenge promoted chromatin remodelling in regions assigned to genes belonging to IFN and TNF signaling pathways as well as response to viral and bacterial pathogens. (D) Rank plot of selected terms. DOC regions tagged genes assigned to “I−kappaB kinase/NF−kappaB signaling,” “TNF signaling,” and “Interferon signaling” pathways. DOCs are plotted according to their log2FC on the x axis and ranked according to the magnitude of change on the y axis. Genes corresponding to opening or closing DOC regions are shown in red and blue, respectively. Horizontal lines indicate the 0.2 log2FC cut off.

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