PT - JOURNAL ARTICLE AU - Andrew R. DiNardo AU - Kimal Rajapakshe AU - Tomoki Nishiguchi AU - Godwin Mtetwa AU - Qiniso Dlamini AU - Jaqueline Kahari AU - Sanjana Mahapatra AU - Alexander Kay AU - Gugu Maphalala AU - Emily Mace AU - Sandra L. Grimm AU - George Makedonas AU - Jeffrey D Cirillo AU - Mihai G. Netea AU - Reinout van Crevel AU - Cristian Coarfa AU - Anna M. Mandalakas TI - Persistent DNA Hyper-methylation Dampens Host Anti-Mycobacterial Immunity AID - 10.1101/805457 DP - 2019 Jan 01 TA - bioRxiv PG - 805457 4099 - http://biorxiv.org/content/early/2019/10/16/805457.short 4100 - http://biorxiv.org/content/early/2019/10/16/805457.full AB - Mycobacterium tuberculosis (Mtb) has co-evolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to shorten existing therapy and improve outcomes will require identifying the full complement by which host immunity is inhibited. Perturbing host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, LCMV and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of TB patients and their asymptomatic household contacts demonstrating that TB patients have DNA hyper-methylation of the IL-2-STAT5, TNF-NF-ϰB and IFN-γ signaling pathways. By MSRE-qPCR, multiple genes of the IL-12-IFN-γ signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1 and JAK2) were hyper-methylated in TB patients. The DNA hyper-methylation of these pathways is associated with decreased immune responsiveness with decreased mitogen induced upregulation of IFN-γ, TNF, IL-6 and IL-1β production. The DNA hyper-methylation of the IL-12-IFN-γ pathway was associated with decreased IFN-γ induced gene expression and decreased IL-12 inducible up-regulation of IFN-γ. This work demonstrates that immune cells from TB patients are characterized by DNA hyper-methylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and non-specific immune responsiveness.