"EpiMacroTB" - Epigenetics of macrophages during Mycobacterium tuberculosis infection

07 August 2017

Project coordinator:

Yulia Medvedeva

Vavilov Instutute of General Genetics; Research Center of Biotechnology RAS, Institute of Bioingeneering


Project partners:

Sanjeev Khosla

Laboratory of Mammalian Genetics, CDFD, Hyderabad


Reto Guler

Division of Immunology, IDM, University of Cape Town

South Africa

Funding agencies:

RFBR (Russia), DST (India), NRF (South Africa)


Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), has re-emerged as a world-wide pandemic causing 1.5 million deaths/year globally. Mtb survives in host macrophages by exploiting several cellular host factors. However it is unclear how Mtb modulates the epigenetic landscape of macrophages to establish a persistence infection. We aim to explore the dynamics of epigenetic and transcriptional modifications and their effector proteins in human macrophages following Mtb infection as well as identify associated noncoding RNAs correlated with these epigenetic changes. To reconstruct epigenetic and expression networks we will perform RNA-seq (transcriptome profiling), with a special focus to epigenetic modifiers including histone methyltransferases and demethylases, and ChIP-seq (histone modifications including active H3K9ac and repressive H3K9me3 or H3K27me3 marks in a time-series experiment (0, 4, 12, 24 and 48 hours post infection) for human monocyte-derived macrophages (MDM) infected either by clinical hypervirulent strain HN878 of Mtb or pathogenic (Mtb, H37Rv), attenuated (M.bovis, BCG), clinically important non-tuberculous opportunistic mycobacteria (M.kansasii or M.phlei) or HIV-Mtb co-infections. The pathogenic and non-pathogenic mycobacteria comparison would identify host-specific convergent and divergent pathways employed by mycobacteria to establish infection and modulating the host immune response. The predicted transcriptional and/or epigenetic regulators will be subjected to shRNA mediated knock-down to score for their roles in regulating mycobacterial infections in terms of entry, persistence and propagation of the bacteria. Surrogate markers associated with appropriate immune response against mycobacteria, like generation of ROS, RNS, NO, acidification of phagosome, released cytokines etc will also be evaluated. Taken together, we aim to identify epigenetics targets hijacked by Mtb as targets for host-directed drug therapies to combat TB.