M.tuberculosis Evading Immunity Decoded
DBT-CDFD Researchers
Insights on how Mycobacterium tuberculosis evades immunity has been decoded by a team of researchers from the Centre for DNA Fingerprinting And Diagnostics (DBT-CDFD), Hyderabad.
Tuberculosis (TB) disease-causing Mycobacterium tuberculosis (M. tuberculosis) continues to survive within what are called macrophages, as it has evolved several adaptive skills and evasion mechanisms to escape the defense system of the body. Usually, macrophages, with the help of an inter-cellular organelle called a lysosome, engulf invading bacteria and kill and digest them. The production of reactive nitrogen species (NO) or reactive oxygen species (ROS) is involved in this process. The destruction of the bacteria is led by this creating oxidative stress. However, this does not happen in the case of Mycobacterium tuberculosis. To avoid oxidative stress caused by NO/ROS, it has evolved strategies.
Now, a protein that seems to limit the oxidative stress-mediated by reactive oxygen species (ROS) or reactive nitrogen species (NO) has been identified by a team of researchers at the Department of Biotechnology’s Centre for DNA Fingerprinting And Diagnostics (DBT-CDFD), Hyderabad. The protein belonged to a family of secretory protein of M. tuberculosis called PPE. The protein named PPE2 has a eukaryotic SH3 domain, a DNA
binding domain, and a monopartite nuclear localization signal (NLS).To interact with a GATA-binding site overlapping with the TATA box of inos promoter and
inhibit NO production, PPE2 is translocated into the macrophage nucleus via the classical importin α/β pathway. The survival of the bacilli in macrophages as well as in a mice infection model is enhanced by PPE2.
The presence of a eukaryotic-like SH3 domain and a PxxP motif in PPE2, in addition to having NLS and DNA binding domain was revealed in the bioinformatics study. The faulty assembly of NADPH oxidase complex and inhibition of ROS production is a result of the PPE2 interacting with the p67phox subunit of NADPH oxidase in the cytosol and hindering the migration of cytosolic subunits p47phox and p67phox from the cytosol to membrane. The researchers mutated conserved residues in the SH3-like domain to alanine (Y209A, W236A, and P249A), deleted a PxxP motif (∆540-543), in PPE2, in order to investigate the role of the SH3-like domain and the PxxP motif in PPE2 mediated ROS inhibition. It was observed that W236A mutation failed to inhibit PPE2-p67phox interaction and could not inhibit ROS generation. This suggested that for PPE2-p67phox interaction, W236 residue in SH3 like the domain of PPE2 is probably crucial.
According to these studies, it is suggested that for the development of novel drugs against M. tuberculosis, PPE2 may be an important target. To diminish oxidative stress, the production of NO and ROS is inhibited by PPE2 in a very coordinated manner. Further studies on PPE2 may help in the development of new drugs to control tuberculosis by understanding the role of oxidative stress in TB pathogenesis and host and mycobacterial interactions.
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M.tuberculosis Evading Immunity Decoded
