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

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 2

AMs display significant differences between groups in transcriptomic response to M. tuberculosis.

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AMs display significant differences between groups in transcriptomic res...
(A) Bar graph summarizing genes that displayed significantly different log2FC between groups (differential M. tuberculosis response). The y axis indicates the cumulative DEG count whereas the x axis indicates the pair-wise group contrast. Dark color shading represents genes with higher response (e.g., M. tuberculosis effect in PLWH vs HC subjects resulted in a positive log2FC difference) while light shading depicts genes with lower response (negative log2FC difference). The union of all gene IDs identified across the 3 contrasts (n = 401) resulted in 333 unique gene IDs. (B) Boxplot for 3 selected pathway/GO terms for genes with significant differential M. tuberculosis response between PLWH or PrEP subjects against controls (n = 302). For each term, the y axis displays the mean log2FC and dots represent per-subject mean value for pooled DEGs. Phenotypic groups are indicated below each box plot across the 3 terms. White dots represent mean log2FC for subjects who do not smoke cigarettes or who have used cannabis, whereas black dots depict smokers and/or cannabis users. To derive the subject mean log2FC, we used pooled DEGs from the first 2 columns in A which were significant for interaction contrasts between PLWH vs HC subjects and PrEP subjects versus HC subjects, obtained subject-wise log2FC for each DEG and averaged the log2FC from all genes per subject. Results showed that group differences are not driven by outliers and that smoking or cannabis consumption do not explain group differences. (C) Manhattan plot for enrichment test of pathways and GO terms from merged DEGs detected in the differential M. tuberculosis responses of PLWH vs HC subjects and PrEP subjects versus HC subjects. The y axis indicates the negative log10 FDR values whereas the tested terms are arranged along the x axis. The horizontal dashed line represents the 10% FDR cut-off for significant pathways/GO terms. Dots are sized as a function of the DEG number in a term and colors represent the database from which the terms were obtained. Identified terms represent innate immune processes and intracellular defense mechanisms. C-type lectin receptors, CLRs.