Wednesday, January 7, 2009

Novel ‘replication check mechanism’ key to dormant Tuberculosis

Tuberculosis is a major communicable disease expanding globally and is caused by Mycobacterium tuberculosis (M. tb). The disease is a main killer among infectious diseases in the world with the occurrence of 2 million deaths each year and 8 million cases of active disease. The biggest challenge of tuberculosis (TB) is its ability to survive in dormant form in apparently healthy individuals for decades. M.tb, the diehard pathogen that causes tuberculosis, is capable of staying asymptomatically in a latent form, persisting for years in very low replicating state, before getting reactivated to cause active infection.

M.tb is known to survive for extended periods during the latency phase without any replication. During this phase the bacterium senses the surrounding environmental conditions such as availability of nutrients, immune cell preponderance etc. and if needed puts its machinery back in action to grow and replicate. The regulation of chromosomal DNA replication therefore is a very important switch to maintain dormancy. While the bacterium is dormant replication is bare minimum.

A new study published by PLoS ONE (In-vitro helix opening of M. tuberculosis oriC by DnaA occurs at precise location and is inhibited by IciA like protein) provides some fresh insights into maintenance of dormancy by the pathogenic mycobacteria. Professor Seyed E. Hasnain (Distinguished Professor at the Institute of Life Sciences at the Hyderabad University campus, Hyderabad, India) who led the study said ‘the dormant state of the bacterium is maintained by a novel protein called as Inhibitor of Chromosomal initiation (IciA), which our group has rigorously characterized and which binds to the A+T rich region of the origin of replication’. ‘This binding blocks helix opening of the A+T rich region, a step critical for chromosomal replication initiation to occur’ says Hasnain. This represents the first evidence that chromosomal DNA replication control is a critical molecular switch in the form of IciA protein, which the TB bacteria over express to remain dormant.

Besides identification of the replication check phenomenon by the IciA, the study also generated an in vitro model of mycobacterial replication which will be a very important tool in the hands of infection biologists trying to understand intricacies of microbial acquisition, survival and adaptation under different stress conditions and in different hosts. Although the present study largely represents laboratory based observations, direct evidence for the role of the IciA like protein will come from M.tb iciA knockout experiments to be performed in an animal infection model. While such experiments are underway at Hasnain labs, it will be interesting to see if quantitative expression of IciA in tuberculosis patient’s material could effectively be harnessed as a molecular marker of M.tb activation.

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