Title

The role of chromosome stability in persistence, latency and reactivation of Mycobacterium tuberculosis

Acronym

CSI-LTB

Contract number

037235

Project type

STREP

EC contribution in Euro

1'000'000 Euro

Starting date

1 March 2007

Duration

24 months

Proposal Abstract

Tuberculosis causes more deaths than almost any other infectious agent, with nearly 2 million deaths each year. One-third of the world's population is latently infected with the causative agent, Mycobacterium tuberculosis. The ability of M. tuberculosis to enter into a latent state is thought to be the reason for the prolonged period of treatment required to prevent relapse, since drugs currently available mainly target actively growing bacteria. The vast pool of latently infected individuals is a constant source of disease and transmission, as factors weakening the immune response, such as HIV infection, lead to the emergence of active disease and infection with TB is a significant cause of AIDS-associated mortality in developing countries. This project suggests to tackle the problem of latency by focusing on the mechanisms that govern chromosome integrity.

 

There is evidence that M. tuberculosis is exposed to DNA-damaging conditions in the hast during latent infection. We hypothesize that M. tuberculosis possesses particularly efficient mechanisms of DNA repair allowing survival until more favourable conditions permit growth, and that these systems are required for the long-term survival of M. tuberculosis within the host. This project aims to evaluate the importance of the mechanisms which maintain genome integrity for bacterial survival during persistence and to identify targets for future drug development. The proposal integrates activities of internationally recognised groups in the field that have complementary expertise to facilitate the multidisciplinary approach required to optimally advance this programme of research. Identification of inhibitors of proteins required for persistence may also lead to the development of new drugs active against bacteria in the latent state. This would be of great value both to shorten the period required to cure the active disease and to treat latent infection in individuals at high risk of disease reactivation.