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Insights into how signalling proteins help tuberculosis bacteria fight stress

Even in today's health-conscious world, with the abundant availability of vaccines and antibiotics, tuberculosis is still among the top health emergencies faced across the globe. This is due to the fact that once infected, Mycobacterium tuberculosis (the bacterium that causes the disease) can survive even under harsh conditions when there is limited supply of nutrients. The bacterium hides for many decades in a dormant form that allows it to persist inside the host without showing any symptoms. This fact, combined with the rise of disease-resistant forms of the bacteria, makes tuberculosis a deadly disease and explains its prevalence until now.

In this context, a new study by researchers at IISc has investigated the regulation of nitrate metabolism by Mycobacterium tuberculosis in order to explain how it survives under low-nutrient conditions. The study was carried out by researchers at the Department of Molecular Reproduction, Development and Genetics (MRDG), IISc, in collaboration with researchers in the US.

“We found that two different proteins which otherwise are part of the different pathways, interact with each other to regulate a more complex environmental condition where multiple stresses might be present at the same time,” explained Dr. Deepak K. Saini, Assistant Professor at MRDG and one of the researchers involved in the study. “Our study allowed us to realize how the bacterium intelligently uses multiple pathways altogether to fight against the unfavourable conditions."

The two proteins they studied, DevR and NarL, help the bacteria to sense various external and internal environmental conditions. DevR is a well-known regulator of dormancy and helps the bacteria to adapt and survive under hypoxia (low-oxygen condition). NarL is believed to be involved in metabolism of nitrate, which is not only a major source of nitrogen inside the host, but also acts as electron acceptor during respiration under the hypoxic condition. The study found that NarL's interactions with DevR allowed the combination to bind to and regulate the expression of genes that are involved in the metabolism of nitrate and transporting toxic nitrite out of the cell. In other words, under extreme conditions of oxygen and nutrient limitation, DevR and NarL work together to help the bacteria adapt and survive, and therefore persist in the host.

This study, therefore, provides insights into the functionality of certain signalling proteins in Mycobacterium tuberculosis and the underlying intricate signaling mechanisms that regulate nitrate metabolism in the bacteria.

These two signalling proteins could potentially be good targets for drug development. Further insights into the complexities of different pathways would allow scientists to come up with smarter solutions to fight against this resilient bacterium. Further research might also allow us to understand how the bacteria survive during dormancy and atypical conditions.


About the authors

The study is a collaborative effort between researchers in India and USA. Deepak K. Saini is an Assistant Professor at the Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India. Ruchi Agrawal is a graduate student in his lab.

Vandana Malhotra, Tammi R. Duncan and Josephine E. Clark-Curtiss are with the Center for Infectious Diseases and Vaccinology, Biodesign Institute, and the School of Life Sciences, Arizona State University, Tempe, Arizona.

The paper appeared in The Journal of Biological Chemistry on 27th March 2015.

Contact: Deepak K. Saini



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