Indian scientists decode how TB bacterium persists in human body


Researchers at the Indian Institute of Science (IISc) in Bengaluru have decoded the mechanism that helps the tuberculosis (TB) bacterium to persist in the human body for decades. In the study, published in the journal Science Advances, they described a single gene that aids in the production of iron-sulphur clusters — key for the persistence of the TB bacterium.

These iron-sulphur clusters help the bacteria in energy production by respiration, and also help it to survive harsh conditions of the lungs and cause infection. TB is caused by the bacterium Mycobacterium tuberculosis (Mtb), which can be present in the human body for decades without any symptoms.

While in many cases, the immune system can detect Mtb and flush it out, sometimes the bug tends to hide within deep oxygen-limiting pockets of the lung and lie in a dormant state, said Mayashree Das, first author and doctoral student at the Department of Microbiology and Cell Biology (MCB), IISc.

“Due to persistence, there is a bacterial reservoir in a subset of the human population at any point which can reactivate and cause infection. Unless we understand persistence, we will not be able to eradicate TB,” said Amit Singh, Associate Professor at MCB and corresponding author of the study, in a statement.

To understand how Mtb builds iron-sulphur clusters, the team grew Mtb in liquid cultures in the lab. Iron-sulphur clusters are mainly produced by the SUF operon in Mtb — a set of genes that get switched on together. However, they found another single gene called IscS that can also produce the clusters.

To explore whether the bacterium needs both, the team generated a mutant version of Mtb without the IscS gene. They found that during normal and oxygen-limiting conditions, the IscS gene produces iron-sulphur clusters. However, oxidative stress damages the clusters, which increases demand for producing more clusters. This switches on the SUF operon.

Further, the team also explored how the IscS gene contributes to disease progression. Mice models were infected with the mutant version of Mtb lacking the IscS gene. The lack of the IscS gene led to severe disease in the infected mice rather than a persistent, chronic infection typically seen in TB patients.

“This is because, in the absence of the IscS gene, the SUF operon is highly activated — albeit in an unregulated fashion — leading to hypervirulence. Depleting both IscS and the SUF system dramatically reduced the persistence of Mtb in mice,” the team said in the study.

They found that the IscS gene keeps the activation of the SUF operon in check, causing persistence in TB. The researchers also noted that bacteria lacking the IscS gene were more likely to be killed by certain antibiotics. “It becomes sensitive to some antibiotics and resistant to some. We would also like to explore this further,” Das said.

The team suggests that combining antibiotics with drugs targeting IscS and SUF might be more effective.

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