BENGALURU: Researchers at the Indian Institute of Science (IISc), in collaboration with National Centre for Biological Sciences (NCBS) and InStem, found an important mechanism that allows the tuberculosis (TB) bacterium to persist in the human host for decades. A single gene involved in the production of iron-sulphur clusters could be crucial for the persistence of TB and its better understanding can eradicate TB.
TB is caused by 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,” said Mayashree Das, first author of the above study and PhD student at the Department of Microbiology and Cell Biology (MCB), IISc. However, in several asymptomatic individuals, Mtb hides within deep oxygen-limiting pockets of the lung becomes dormant and is metabolically inactive– saving itself from the immune system and TB drugs.
“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,” explained Amit Singh, Associate Professor at MCB and corresponding author of the study.
The team grew Mtb in liquid cultures containing special supplements needed for its growth at the Center for Infectious Disease Research (CIDR), IISc. Several proteins in Mtb depend on iron-sulphur clusters for functioning. “The clusters containing proteins are important for essential processes such as energy production by respiration, enabling the bacteria to survive harsh conditions of the lungs and causing infection,” said Singh.
However, there is another single gene called IscS that can also produce the clusters. To find a correlation among them the researchers generated a mutant version of Mtb that lacked the IscS gene. Under normal and oxygen-limiting conditions, iron-sulphur clusters are produced mainly by the action of the IscS gene.
However, when the bacterium faces a lot of oxidative stress, the iron atoms of the clusters become oxidised and released, damaging the clusters which leads to increased demand for producing more clusters.
Scientists infected mice models with the mutant version of Mtb lacking the IscS gene which led to severe disease but not chronic infection seen in TB patients. This is because, in the absence of the IscS gene, the SUF operon is highly activated leading to hypervirulence.
The team found that the IscS gene keeps the activation of the SUF operon in check, causing persistence.
Researchers suggested that combining antibiotics with drugs targeting IscS and SUF might be more effective. Singh is hopeful that a better understanding of the IscS and SUF systems in Mtb can eventually help eradicate the persistence of TB. The study was published in Science Advances.