Post TB DNA hypermethylation of an epigenetic network correlates with improved lung function 3769

Abstract Description After successful TB therapy, 10-20% patients have worsening lung function. DNA methylation are heritable epigenetic marks that regulate immunity. We previously reported that TB induced persistent DNA hypermethylation scars limiting Mtb-specific peptide ESAT-6 and non-specific BCG / mitogen immunity. How DNA methylation affects lung function recovery during TB therapy is unknown. Leveraging PBMCs from a completed clinical trial, DNA was isolated from 73 micro-confirmed TB participants; despite successful therapy 44% had worse FEV1 or FVC. Declining inflammation, measured by CRP, only weakly correlated with improved lung function. DNA methylation assayed via Epic Array was aggregated at coding genes 200 bases upstream of TSS, then pathway z-scores were computed. Improved lung function correlated with DNA hypermethylation of Inflammation, Interferon-gamma, TNF, IL-6, and p53 pathways. WGCNA analysis identified a hypermethylated 236 gene module, termed “red”, correlated with FEV1/FVC change r = 0.3, p = 0.01, including CXCR5, CD27, TREM1, and TREM2. The red module correlated with improved FEV1, immune response via quantiferon assay, change in glucose, and inversely correlated with smoking status. The immune system must balance killing intracellular pathogens without inducing tissue pathology. This work suggests DNA hypermethylation limits intracellular mycobacterial killing capacity in order to prevent immune-induced lung pathology. Funding Sources Supported by National Institute of Allergy and Infectious Diseases (NIAID) K23 AI141681A, 1R01AG078268-01A1,and 1R01AI70774-01A1 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)