Alveolar macrophages from persons living with HIV show impaired epigenetic response to Mycobacterium tuberculosis
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
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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Research Article AIDS/HIV Infectious disease

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

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 1

Study design and differential gene expression by AMs in response to M. tuberculosis.

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Study design and differential gene expression by AMs in response to M. t...
(A) Experimental design and sample number by group. Each subject underwent BAL. AMs were obtained from BAL and challenged in vitro with M. tuberculosis for 18 to 20 hours. RNA was obtained for RNA-Seq, whereas DNA was used for ATAC-Seq and ChIP-Seq experiments. (B) Bar graph summarizing DEGs by AM, following M. tuberculosis challenge across the 3 phenotypic groups (HCs; PLWH on antiretroviral therapy; PrEP subjects). The y axis indicates the cumulative DEG count and group ID is indicated below each bar. Dark color shades represent upregulated genes (positive log fold-change; log2FC) whereas light shades depict downregulated genes (negative log2FC). (C) Density plot presenting log2FC as absolute values. All DEGs from B had their log2FC converted to absolute values and plotted using density function. Vertical colored lines indicate the median of absolute values per group, with exact values given on top. Blue shade represents HC subjects, red indicates PLWH, and green indicates PrEP subjects. (D) Dot plot presenting significance and overall effect for selected pathways and GO terms. Pathways/GO terms are listed on the left, dot sizes reflect the negative log10 FDR values for the enrichment test (bigger dots have smaller P values) and colors from red (higher value) to blue (lower value) indicate the median log2FC across all detected genes in the corresponding pathway or GO term. To derive the average log2FC for a pathway/GO term, for each group we identified the corresponding DEGs, pooled all gene IDs from the 3 groups, retrieved the log2FC for each of these genes, and established the median of log2FC per group.