Indian researchers find key mechanism that allows TB bacterium to hide in humans for decades

TB is caused by the bacterium Mycobacterium tuberculosis (Mtb), which can be present in the human body for decades without any symptoms.

ByChetana Belagere

Published Dec 26, 2023 | 7:00 PMUpdatedDec 26, 2023 | 7:00 PM

TB bacterium humans

Scientists in India have made an important discovery about how tuberculosis (TB) bacteria can stay inside a person’s body for many years without being detected.

TB is caused by the bacterium Mycobacterium tuberculosis (Mtb), which can be present in the human body for decades without any symptoms.

“Mtb needs humans to survive. In many cases of Mtb infection, the immune system can detect the bug and clear it out,” explains Mayashree Das, lead author and PhD student at the Department of Microbiology and Cell Biology (MCB) at the Bengaluru-based Indian Institute of Science (IISc) in a release.

However, in several asymptomatic individuals, Mtb hides within deep oxygen-limiting pockets of the lung and enters a state of dormancy in which it does not divide and is metabolically inactive. In doing so, it successfully hides from the immune system and TB drugs.

Scientists from the IISc, in collaboration with the National Centre for Biological Sciences (NCBS) and the Institute for Stem Cell Science and Regenerative Medicine (InStem), have uncovered a critical mechanism that enables the TB bacterium to remain dormant within the human body for extended periods.

Their findings, published in the journal Science Advances, shed light on a single gene’s role in the persistence of the TB bacterium. This new research can help scientists to find better ways to fight TB.

Related: Study suggests simple, rapid blood test can diagnose TB in children

TB’s hidden threat

Scientists have long sought to understand how Mtb evades the body’s immune system and resists treatment. This new research reveals a crucial piece of the puzzle.

Mayashree Das from IISc, one of the lead authors of the study, explained that while the human immune system can often detect and eliminate the TB bacterium, it manages to hide in oxygen-deprived areas of the lungs in some individuals, becoming dormant and metabolically inactive.

This dormancy shields it from both the immune system and TB drugs, she explained.

Amit Singh, an associate professor at the Department of Microbiology and Cell Biology at IISc and the study’s corresponding author, highlighted the importance of understanding this persistence mechanism.

He said this leads to a reservoir of the bacterium within the human population that is capable of reactivating and causing infections. This means this hidden bacteria can potentially wake up and make people sick again.

To effectively fight TB, the medical community needs to find a way to deal with this hidden and reactivating aspect of the disease, explained the authors.

Related: National TB elimination programme includes India’s 1st MDR test 

What is the mechanism?

According to the release from the IISc, Singh’s team conducted experiments in a state-of-the-art bio-safety Level-3 facility, growing Mtb in controlled conditions.

They focused on proteins in the bacterium that rely on iron-sulphur clusters for their function.

These clusters made up of iron and sulphur atoms arranged in various configurations, play a role in crucial cellular processes like respiration and energy production.

“The iron-sulphur cluster-containing proteins are essential for the bacterium’s survival in the harsh lung environment, enabling it to cause infection. So, we wanted to understand how Mtb produces these clusters,” the release said.

Related: Mangaluru physician couple expose blind spot in India’s TB care

A dual gene mystery

The research revealed that these clusters are primarily produced by the “IscS” gene in Mtb under normal conditions.

However, when the bacterium faces oxidative stress, the clusters become oxidised and damaged, increasing the need for more clusters. This activates another set of genes, known as the SUF operon (SUF).

This simply means, imagine the TB bacteria as tiny machines that need a special tool called “iron-sulphur clusters” to work properly. Normally, they make these tools using a gene called “IscS.”

But when these bacteria get stressed, like when our body’s defence system tries to attack them, the tools get damaged. So, they need even more tools to keep working. This is when another group of genes called “SUF Operon” comes into action.

To understand this better, scientists made a version of the TB bacteria that couldn’t use the “IscS” gene.

The release explained that the researchers created a mutant version of Mtb lacking the “IscS” gene. When they did this, the absence of this gene resulted in severe disease in mice models, as the “SUF operon” was overly activated, leading to hypervirulence. Which means the mice they infected became very sick.

However, when they removed both the “IscS” gene and the “SUF operon” genes, the MTB bacteria became weak and couldn’t hide anymore.

In simple terms, it’s like the “IscS” gene acts as a control switch that keeps the bacteria from getting too powerful.

When it’s turned off, the bacteria become less dangerous.

Promising implications

Additionally, the study found that bacteria lacking the “IscS” gene were more susceptible to certain antibiotics.

This intriguing discovery suggests that combining antibiotics with drugs targeting “IscS” and “SUF” may be a more effective strategy in treating TB.

Amit Singh said he was hopeful that a deeper understanding of the “IscS” and “SUF” systems in Mtb could eventually pave the way for eradicating TB persistence.

This research represented a significant step forward in the fight against this persistent and devastating disease, he said.