Key Mechanism Behind Tuberculosis Longevity Revealed

A study led by Indian Institute of Science researchers has identified a crucial mechanism enabling the tuberculosis (TB) bacterium to endure within the human host for extended periods. The research, detailed in Science Advances, implicates a single gene responsible for the production of iron-sulphur clusters as potentially pivotal for the TB bacterium's persistence.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), can persist in the human body for decades without symptoms. The study reveals that in asymptomatic individuals, Mtb conceals itself in oxygen-deprived lung pockets, entering a dormant state to evade the immune system and traditional TB drugs, emphasizing the importance of understanding this persistence for effective TB eradication.

Several proteins in Mtb depend on iron-sulphur clusters for functioning. These clusters consist of iron and sulphur atoms organized in various configurations like chains or cuboids. The iron atoms in the cluster can pass on electrons from one site of a protein complex to another in cellular reactions such as respiration and carbon metabolism. 

Iron-sulphur clusters are mainly produced by the SUF operon in Mtb, a set of genes that get switched on together. However, there is another single gene called IscS that can also produce the clusters. So why would the bacterium need both?  

To solve this mystery, the researchers generated a mutant version of Mtb that lacked the IscS gene. They found that 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 oxidized and released, damaging the clusters. Therefore, there is an increased demand for producing more clusters, which switches on the SUF operon.  

The researchers then sought to find out how the IscS gene contributes to disease progression. They infected mice models with the mutant version of Mtb lacking the IscS gene. The absence 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 leading to hypervirulence. Depleting both IscS and the SUF system dramatically reduced the persistence of Mtb in mice. Therefore, the team found that the IscS gene keeps the activation of the SUF operon in check, causing persistence in TB.  

Furthermore, bacteria without the IscS gene exhibited altered sensitivity to antibiotics, suggesting potential avenues for combination therapies. The team proposes exploring drugs targeting both IscS and SUF, anticipating enhanced effectiveness. This deeper understanding of the IscS and SUF systems in Mtb offers hope for eradicating