Understanding how Mycobacterium tuberculosis tackles oxidative stress in the host

About author: Dr. Mehak Zahoor Khan pursued her bachelor’s and masters in Biochemistry from the University of Delhi. Subsequently, she joined Dr. Vinay K. Nandicoori’s research group at the National Institute of Immunology for her Ph.D. During her doctorate, she worked on multiple projects extending from kinase signaling, transcription, metabolism, and virulence to the process of mycobacterial cell division. As a lead author, she published four peer-reviewed articles and a review. Here, Mehak talks about her latest work, “Redox homeostasis in Mycobacterium tuberculosis is modulated by a novel actinomycete-specific transcription factor,” recently published in EMBO J.

How would you explain your research outcomes to the non-scientific community?

Tuberculosis has existed since immemorial times, and its history has mystified science ever since. Mycobacterium tuberculosis (Mtb) was discovered as the etiological (causative) agent of tuberculosis in 1882. Despite the clinical use of a vaccine and multiple antibiotics, Mtb claims ~1.3 million lives per year. At present, India alone accounts for 27% of the total TB cases, and hence deciphering mechanisms by which Mtb survives inside the host has always been our lab’s central focus.

All living organisms fine-tune their gene expression in cue with local environmental cues and growth conditions. This study aimed to understand how Mtb modulates its gene expression to successfully survive inside the antagonistic host cells.

Figure: The host produces copious amounts of reactive oxygen and nitrogen species via the IFN gamma pathway in response to Mtb infection.
Oxidative stress induces the formation of an intrasubunit disulfide bond in AosR.
AosR interacts with an extracytoplasmic-function sigma factor, SigH, and promotes transcription of non-canonical cysteine biosynthesis pathway through an auxiliary stress-responsive promoter.
The AosR-SigH signaling axis facilitates the ability of Mtb to subvert oxidative and nitrosative stress, enhancing bacillary survival.

How do these findings contribute to your research area?

Not only have we identified a novel genetic determinant, AosR, that facilitates Mtb’s survival within the host, 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. It would be interesting to develop AosR specific inhibitors and test their ability to inhibit Mtb’s growth as a part of adjunct therapy.

What was the exciting moment during your research?

At the start of the project, one of our major hypotheses was that AosR regulates its own promoter during oxidative stress. However, experimental results proved it to be wrong. The most exciting moment during this project was when we could rationalize why that might be happening. We found that AosR regulates an auxiliary intragenic promoter only during stress-specific conditions.

What do you hope to do next?

Currently, I am working as a research associate to understand the specific role of various cysteine synthases encoded by Mtb. Next, I am hoping to join the University of Toronto by year-end to broaden my scientific expertise.

Where do you seek scientific inspiration from?

My scientific inspiration lies in “Knowing the unknown.” The joy of having to discover something novel is unbeatable. Pursuing science, in my view, is quite similar to solving a giant, highly complex puzzle. I draw immense pleasure as I, along with my team, solve each puzzle piece.

How do you intend to help Indian science improve?

As an early career researcher, we should primarily put forth our best efforts to help Indian science grow. Setting up national and international collaboration is also a great way to improve and promote science and technology in India.

Reference

Mehak Zahoor Khan, Biplab Singha, Mohammad Farhan Ali, Khushman Taunk, Srikanth Rapole, Samudrala Gourinath, Vinay Kumar Nandicoori. Redox homeostasis in Mycobacterium tuberculosis is modulated by a novel actinomycete-specific transcription factor. The EMBO Journal (2021) 40: e106111. https://doi.org/10.15252/embj.2020106111

Edited by: Manveen K Sethi

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