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TB bacteria can persist in human hosts for decades
Scientists found that the gene IscS could produce iron-sulphur clusters essential for the persistence of tuberculosis bacterium in human hosts
Representative image of lung infection / image - iStock
Researchers at the Indian Institute of Science (IISc) have uncovered an important mechanism that allows the tuberculosis (TB) bacterium to persist in a human host for decades.
The team including researchers from the National Centre for Biological Sciences (NCBS) and Institute for Stem Cell Science and Regenerative Medicine (InStem), Bengaluru, collaborated with IISc scientists to find that a single gene is involved in the production of iron-sulphur clusters which could be crucial for the persistence of the TB bacterium, as per a new study.
The disease is caused by a bacterium identified as Mycobacterium tuberculosis (Mtb). In many cases of Mtb infection, the immune system usually helps clear the bacteria out, as per Mayashree Das, first author of the study. However, in several asymptomatic individuals, Mtb hides deep within oxygen-limiting pockets of the lung and enters a state of dormancy.
The bacteria does not multiply and remains metabolically inactive, which allows it to stay undetected by the immune system and TB medication.
“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, corresponding author of the study.
Singh’s team grew Mtb in liquid cultures containing special supplements essential for its growth, at the Center for Infectious Disease Research (CIDR), IISc. Several proteins in Mtb depend on iron-sulphur clusters for functioning. These clusters contain iron (Fe) and sulphur (S) atoms, and the former can pass on electrons from one site of a protein complex to another during cellular reactions like respiration and carbon metabolism.
“The iron-sulphur cluster-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. So, we wanted to study the mechanisms that Mtb uses to build these iron-sulphur clusters,” Singh explained.
Fe-S clusters are mainly produced by the SUF operon in Mtb, a set of genes that get switched on together, researchers said. However, there is another single gene called IscS that can also produce the Fe-S clusters, they said. To explain why Mtb needs the SUF operon as well as the IscS gene, researchers in this study generated a mutant version of Mtb that lacked the IscS gene.
It was found that under normal and oxygen-limiting conditions, the Fe-S clusters were majorly produced by the IscS gene, however, oxidative stress damaged the clusters, resulting in an increased demand for producing more clusters. This is when the SUF operon switches on.
The researchers then sought to find our how the IscS gene contributes to development of the disease, by infecting mice with a mutant version of Mtb lacking the gene. The absence of IscS gene led to severe disease in the mice, compared to a persistent chronic infection typically seen in TB patients. This is because in the absence of IscS, the SUF operon become hyperactive and produces clusters, unregulated, leading to hypervirulence.
It was hence deduced that the IscS gene was essential to keep the activation of the SUF operon in check, causing persistence in TB.
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