A breakthrough study by researchers at the Indian Institute of Science (IISc) has successfully deciphered the mechanism that enables the tuberculosis (TB) bacterium to endure within the human body for extended periods. Published in the journal Science Advances, the study highlights a singular gene responsible for facilitating the production of iron-sulphur clusters, crucial for the TB bacterium’s persistence.
These iron-sulphur clusters play a vital role in the bacterium’s energy production through respiration, allowing it to survive the harsh conditions of the lungs and cause infections. Mycobacterium tuberculosis (Mtb), the bacterium responsible for TB, can persist in the human body for decades without exhibiting any symptoms.
While the immune system can often detect and eliminate Mtb, the bacterium sometimes hides within oxygen-limiting pockets of the lungs, lying dormant. Mayashree Das, the study’s first author and a doctoral student at the Department of Microbiology and Cell Biology (MCB), IISc, explained that this persistence leads to a bacterial reservoir that can reactivate and cause infection, making understanding persistence crucial for eradicating TB.
Amit Singh, Associate Professor at MCB and the corresponding author of the study, emphasized the necessity of comprehending persistence to tackle TB effectively. To investigate how Mtb forms iron-sulphur clusters, the researchers cultivated Mtb in liquid cultures in the lab. While the SUF operon is traditionally responsible for producing these clusters, the study revealed a single gene, IscS, capable of independently generating them.
By creating a mutant version of Mtb lacking the IscS gene, the researchers observed that under normal and oxygen-limiting conditions, IscS produced iron-sulphur clusters. Oxidative stress damaged these clusters, leading to increased demand and the subsequent activation of the SUF operon. The absence of the IscS gene resulted in heightened virulence and severe disease in infected mice, deviating from the typical chronic infection seen in TB patients.
The IscS gene was found to regulate the SUF operon’s activation, contributing to TB persistence. Moreover, bacteria lacking the IscS gene displayed increased susceptibility to certain antibiotics. The researchers propose that a combination of antibiotics and drugs targeting IscS and SUF could be a more effective approach.
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