Tuberculosis is a disease of major importance with about 10 million new case and 3 million deaths annually worldwide. In the United States, the incidence of tuberculosis is comparatively low but has shown an alarming increase in the past few years, reversing a decline over the 32 years. This increase is coincident with the AIDS epidemic, and a high proportion of AIDs patients suffer from infection with Mycobacterium tuberculosis. Moreover, HIV infection can convert latent M. tuberculosis infections to chronic tuberculosis. AIDS patients are also susceptible to opportunistic infection by Mycobacterium avium, which responds poorly to antibiotics and contributes to a significant proportions of deaths among AIDS sufferers. Leprosy afflicts about 12-15 million people worldwide, mostly but not exclusively, in tropical and subtropical regions causing serve physical deformity in about one third of patients. Leprosy is caused by chronic infection of Mycobacterium leprae, one of the few human pathogens that has not been successfully grown in vitro, and thus very poorly characterized. Tuberculosis and leprosy can be controlled through the use of antibacterial drugs, although the regimens are lengthy and relatively expensive. BCG (Mycobacterium tuberculosis typus bovinus var. Bacille-Calmette Guerin), one of the most widely used vaccines, offers protection against tuberculosis and/or leprosy, with efficacy that varies with geographical location. However, the widespread use of BCG makes it a potential host for the construction of recombinant vaccines with novel specificities. There is an urgent need for more effective vaccines and drugs to control mycobacterial diseases. Progress to this goal would be greatly facilitated through a fuller understanding of mycobacteria, mechanisms of their pathogenesis and their response to antimycobacterial drugs. In particular, mycobacteria are poorly characterized genetically, and the long term aim of this project is to obtain an understanding of how mycobacterial genes are organized, how they are expressed, and how they can be manipulated. The tools of molecular biology offer a promising route to the construction of new and better drugs and vaccines, and improved methods for diagnosis.
The aim of this proposal is to investigate gene expression and its regulation in the temperate mycobacteriophage PH39 and its host Mycobacterium smegmatis. The complete DNA sequence of phage PH39 will be determined and its transcriptional promoters characterized in vivo and in vitro. Cloning vehicles for the isolation of bacterial promoters will be constructed and used for characterizing both phage and bacterial transcriptional elements.
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