![]() ![]() To obtain the contiguous genome sequence, a combined approach was used that involved the systematic sequence analysis of selected large-insert clones (cosmids and BACs) as well as random small-insert clones from a whole-genome shotgun library. An integrated map of the 4.4 megabase (Mb) circular chromosome of this slow-growing pathogen had been established previously and ordered libraries of cosmids and bacterial artificial chromosomes (BACs) were available 7, 8. tuberculosis has found extensive, worldwide application in biomedical research because it has retained full virulence in animal models of tuberculosis, unlike some clinical isolates it is also susceptible to drugs and amenable to genetic manipulation. Since its isolation in 1905, the H37Rv strain of M. tuberculosis is either unusually inert or that the organism is relatively young in evolutionary terms. On the basis of the systematic sequence analysis of 26 loci in a large number of independent isolates 6, it was concluded that the genome of M. ![]() This is important in terms of immunity and vaccine development as most of the proteins will be identical in all strains and therefore antigenic drift will be restricted. The complex lacks interstrain genetic diversity, and nucleotide changes are very rare 6. microti, arose from a soil bacterium and that the human bacillus may have been derived from the bovine form following the domestication of cattle. It is thought that the progenitor of the M. Little is known about the mechanisms involved in life within the macrophage, or the extent and nature of the virulence factors produced by the bacillus and their contribution to disease. Novel biosynthetic pathways generate cell-wall components such as mycolic acids, mycocerosic acid, phenolthiocerol, lipoarabinomannan and arabinogalactan, and several of these may contribute to mycobacterial longevity, trigger inflammatory host reactions and act in pathogenesis. tuberculosis, a Gram-positive bacterium with a G + C-rich genome, contains an additional layer beyond the peptidoglycan that is exceptionally rich in unusual lipids, glycolipids and polysaccharides 4, 5. The molecular basis of dormancy and reactivation remains obscure but is expected to be genetically programmed and to involve intracellular signalling pathways. As immunity wanes, through ageing or immune suppression, the dormant bacteria reactivate, causing an outbreak of disease often many decades after the initial infection 3. ![]() The state of dormancy in which the bacillus remains quiescent within infected tissue may reflect metabolic shutdown resulting from the action of a cell-mediated immune response that can contain but not eradicate the infection. This contributes to the chronic nature of the disease, imposes lengthy treatment regimens and represents a formidable obstacle for researchers. tuberculosis, in synthetic medium or infected animals, is typically ∼24 hours. The characteristic features of the tubercle bacillus include its slow growth, dormancy, complex cell envelope, intracellular pathogenesis and genetic homogeneity 2. The combination of genomics and bioinformatics has the potential to generate the information and knowledge that will enable the conception and development of new therapies and interventions needed to treat this airborne disease and to elucidate the unusual biology of its aetiological agent, Mycobacterium tuberculosis. Radical measures are needed now to prevent the grim predictions of the WHO becoming reality. In 1993, the gravity of the situation led the World Health Organisation (WHO) to declare tuberculosis a global emergency in an attempt to heighten public and political awareness. Recent years have seen increased incidence of tuberculosis in both developing and industrialized countries, the widespread emergence of drug-resistant strains and a deadly synergy with the human immunodeficiency virus (HIV). Despite the availability of effective short-course chemotherapy (DOTS) and the Bacille Calmette-Guérin (BCG) vaccine, the tubercle bacillus continues to claim more lives than any other single infectious agent 1. ![]()
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