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.
View: Text | PDF
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

×

Figure 4

Histone H3K27 acetylation changes in response to M. tuberculosis.

Options: View larger image (or click on image) Download as PowerPoint
Histone H3K27 acetylation changes in response to M. tuberculosis. (A) V...
(A) Volcano plots for H3K27 acetylation response to M. tuberculosis. Chromatin regions significantly DAc at a FDR less than 5% and absolute log2FC greater than or equal to 0.2 after M. tuberculosis challenge are colored, with higher acetylation of H3K27 in red and lower acetylation in blue. The numbers of DAc regions are given at the top. Significant changes in H3K27 acetylation, indicating active enhancers, were observed mostly for the HC group, which encompassed 7 subjects compared with 11 PLWH on antiretroviral therapy and 6 PrEP subjects. Additionally, the magnitude of log2FC was higher in HC subjects compared with PLWH and PrEP subjects. (B) Density of the absolute log2FC for 2731 DAc regions detected in at least one group is shown for HC, PrEP, and PLWH groups in blue, green, and red, respectively. Mean log2FC for each group is highlighted by vertical lines. PrEP and PLWH groups showed strongly reduced changes in H3K27 acetylation in response to M. tuberculosis compared with the HC group. (C) Enrichment analysis of genes assigned to regions with increased H3K27 acetylation for the HC subjects, PLWH, and PrEP subjects response to M. tuberculosis. GO BP, KEGG, and Reactome pathways with at least 5 assigned genes are plotted against the negative log10 FDR. As observed for the chromatin changes, enrichment analysis indicated that in AMs of HC subjects, M. tuberculosis challenge promoted increased acetylation in more regions assigned to genes belonging to IFN and TNF signaling pathways as well as response to viral and bacterial pathogens. Terms highlighted in red are those for which we showed differential M. tuberculosis response between PLWH or PrEP subjects against HC subjects in Figure 2B.