Newer Insights Into An Age Old Bacteria
BY RATNESHWAR THAKUR
Researchers from DBT-NII has identified a novel transcription factor named as AosR and their experimental results provides novel insights towards understanding its physiological role in subverting host innate response.
Despite decades of research on the Mycobacterium tuberculosis (Mtb), a bacterium that causes tuberculosis (TB), scientists have not had a complete understanding of how the Mycobacterium tuberculosis survives inside the host. India alone accounts for 27% of the total TB cases (WHO report, 2018) and hence deciphering mechanisms by which Mtb survive inside the host has always been centre focus for the various labs across India.
All living organisms fine-tune their gene expression according to the changing local environment and growth conditions. Now, researchers at the National Institute of Immunology (NII), New Delhi – have taken the steps to understand how Mtb modulates its gene expression in order to successfully survive inside the hostile host cells.
The research team led by Dr. Vinay K. Nandicoori at DBT-NII has identified a novel transcription factor named as AosR (Actinomycetes oxidative stress Regulator) and their experimental results, published in ‘The EMBO journal,’ provides novel insights towards understanding its physiological role in subverting host innate response. Here transcription factors are proteins and their actions allows unique expression of each gene in different cell types in living organisms.
In this study, researchers explored available Transposon-sequencing datasets to identify transcription factors that are essential for Mtb survival inside the host. Here transposons are class of DNA sequences that can “jump” to different locations within a genome. Interestingly, they found a single transcription factor, AosR as a factor conserved across actinomycetes and so-far their functions are not well studied.
According to the research team, AosR mitigates host-derived oxidative and nitrosative stress, thus promoting mycobacterial growth in the host. In an attempt to seek the underlying mechanism, the team found that oxidative stress induces the formation of a single intrasubunit disulphide bond in AosR. This in-turn facilitates its interaction with an extra-cytoplasmic-function sigma factor, SigH. Further, it results in specific up-regulation of the CysM-dependent unusual cysteine biosynthesis pathway through stress-responsive promoter.
“Not only have we identified a novel genetic determinant that facilitates Mtb’s survival within the host, but we were also able to deduce the underlying mechanism (signal for its activation, interaction partner, binding site, and target genes). The study broadens our understanding of how Mtb employs unique transcriptional networks and metabolic pathways to self-serve its nutritional needs whilst effectively combating the host immune system,” said Mehak Zahoor Khan, lead author in this study.
“We believe that the results of this study unearth new facets of the Mtb-host relationship and underscore the novel mechanisms this pathogen has evolved to get the better of its hostile host,” she added.
The research team included Mehak Zahoor Khan, Biplab Singha, Mohammad Farhan Ali, Khushman Taunk, Srikanth Rapole, Samudrala Gourinath, and the study was led by Vinay Kumar Nandicoori.
“We have shown that inhibition of the novel redox-sensing regulatory network impacts global gene expression in this pathogen. It dampens the pathogen’s ability to combat host-induced redox stress, thus weakens its survival in the host,” said Dr. Vinay K. Nandicoori, senior scientist at NII, New Delhi. Dr. Nandicoori is currently heading as the director of CSIR–Centre For Cellular And Molecular Biology (CSIR–CCMB), Hyderabad.”