SRA

DNA from an outside collaborator for DNA sequencing. Tuberculosis is the leading cause of infectious disease mortality in the world. Effectively combating this re-emerging disease in the United States requires deep knowledge about the strains in the vast global reservoir of M. tuberculosis. The availability of genome sequence from three strains of M. tuberculosis has already provided some insights into the metabolic pathways and pathogenic nature of the organism. However, many fundamental questions pertaining to the spread and treatment of the disease remain, including the full range of mechanisms of drug resistance, the fitness of drug-resistant organisms, and the transmissibility, immunogenicity and virulence of the organism. Although the development of molecular genetic tools for mycobacteria has helped identify many of the genes involved in drug resistance and some putative genes associated with highly successful strains, numerous important issues surrounding the transmissibility, immunogenicity, virulence and drug resistance of M. tuberculosis remain unresolved. These issues can best be addressed through the identification of: - previously unrecognized mutations leading to drug resistance; - compensatory mutations that may restore fitness to organisms that have acquired drug resistance; - polymorphic genes associated with transmissibility, immunogenicity and virulence. We propose to sequence 12 carefully selected strains of M.tuberculosis and exploit comparative approaches to understand the genetic basis for observed differences in critical aspects of the infectious behavior of these strains. Understanding these differences in behavior is the first step to designing more effective therapeutics, vaccines, and diagnostic tools that will help stem the spread of this re-emerging disease