DNA hypermethylation during tuberculosis dampens host immune responsiveness
Andrew R. DiNardo, … , Cristian Coarfa, Anna M. Mandalakas
Andrew R. DiNardo, … , Cristian Coarfa, Anna M. Mandalakas
Published March 3, 2020
Citation Information: J Clin Invest. 2020;130(6):3113-3123. https://doi.org/10.1172/JCI134622.
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DNA hypermethylation during tuberculosis dampens host immune responsiveness

Abstract

Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited. Perturbation of host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, lymphocytic choriomeningitis virus (LCMV), and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of patients with tuberculosis (TB) and their asymptomatic household contacts and found that the patients with TB have DNA hypermethylation of the IL-2/STAT5, TNF/NF-κB, and IFN-γ signaling pathways. We performed methylation-sensitive restriction enzyme–quantitative PCR (MSRE-qPCR) and observed that multiple genes of the IL-12/IFN-γ signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1, and JAK2) were hypermethylated in patients with TB. The DNA hypermethylation of these pathways was associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-γ, TNF, IL-6, CXCL9, CXCL10, and IL-1β production. The DNA hypermethylation of the IL-12/IFN-γ pathway was associated with decreased IFN-γ–induced gene expression and decreased IL-12–inducible upregulation of IFN-γ. This study demonstrates that immune cells from patients with TB are characterized by DNA hypermethylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and nonspecific immune responsiveness.

Authors

Andrew R. DiNardo, Kimal Rajapakshe, Tomoki Nishiguchi, Sandra L. Grimm, Godwin Mtetwa, Qiniso Dlamini, Jaqueline Kahari, Sanjana Mahapatra, Alexander Kay, Gugu Maphalala, Emily M. Mace, George Makedonas, Jeffrey D. Cirillo, Mihai G. Netea, Reinout van Crevel, Cristian Coarfa, Anna M. Mandalakas

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Figure 2

Global DNA methylation perturbations persist 6 months after successful ATT.

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Global DNA methylation perturbations persist 6 months after successful A...
The Illumina DNA Methylation EPIC array was performed on bulk PBMCs from asymptomatic household contacts (n = 10) and individuals with TB (n = 15; TB/HIV– = 7; TB/HIV+ = 8) at baseline. All individuals with TB had treatment success. For individuals without HIV coinfection, DNA methylation status was evaluated at baseline and 12 months later, 6 months after completion of successful ATT. (A) To ascertain the immune cell–specific DNA methylation changes, cell-specific DNA methylation reference profiles were downloaded from public archives, informative loci were identified, and cell type–specific methylation profiles were identified. (B) Cell-specific DNA methylation differences are shown for TB patients (base) and TB/HIV (HIV) patients at baseline and for TB patients 12 months after baseline (12 mo), 6 months after completion of successful ATT. All results were compared with HC data. GO pathway analysis for monocytes (CD14+), Th cells (CD3–CD4+), NK cells (CD3–CD56+), and CTLs (CD3+CD8+). (C and D) Purified Th cells (CD3+CD4+) (n = 2) and EDEC-identified Th cells (CD3+CD4+) (n = 8 TB patients; n = 10 controls) were compared with cells from controls, and common hypermethylated pathways and genes were identified.