Editorial [Hot Topic: Tuberculosis (Part 1) (Guest Editor: Douglas B. Lowrie)]

It is some twenty years since the first genes were cloned from pathogenic mycobacteria and 8 years since the complete DNA sequence of a Mycobacterium tuberculosis genome was published. When the first genes were cloned TB was commonly regarded as a beaten disease; we had fully effective chemotherapy, an adequate vaccine (BCG) and the remaining problem (people dying elsewhere) was to be solved by field operational and socio-economic developments. The declaration by the World Health Organization in 1993 that tuberculosis had become “A Global Emergency” certainly helped to change the perception that TB was a beaten disease and, although the emphasis remained on the operational issues of improving the application of the existing control measures, particularly DOTS chemotherapy, there was a surge in basic research. This is fortunate, since there has been little sign that the global emergency (2 million deaths a year) is coming under control by application of the existing tools. On the contrary, extremely drug resistant (XDR) TB is disseminating, bringing with it the 40-60% death rates that prevailed in the pre-chemotherapy era. Equally, there is no sign that the synergy between HIV and TB that is devastating some parts of the world, and spreading, is being brought under control either. There is typically a long lag between basic research and applied benefits and the length of that lag is inversely proportional to the financial resources mobilized. The resources have been paltry in relation to the scale of the problem and the benefits to be gained. Yet, already we have attained a dramatically increased understanding of the bacterium and how it goes about its business of growing, causing disease and spreading. Conceptual changes have been brought about and new drugs and new vaccines have been devised. Many of these are reviewed in this issue of the journal. The first four reviews deal with basic studies of the mycobacterium, which may underpin and inform efforts directly aimed at developing new practical tools for disease control. Cox and Cook have drawn together remarkable new insights into the metabolic pathways and growth regulation of the tubercle bacillus and derived mathematical relationships between key variables. Dover et al. provide a comprehensive review of the detailed level at which the synthesis of the complex cell wall is now understood and Bacon and Marsh review the unexpected ways in which the bacteria respond to controlled changes in single environmental variables. Waddell and Butcher discuss the evidence and implications of the findings that the metabolism of the bacterium inside infected cells is dramatically different from its metabolism in conventional laboratory conditions. Whereas the basic studies can be viewed as providing the basis for rational design of new tools, particularly bactericidal drugs aimed at key aspects of bacterial persistence and growth in vivo, the extent to which this is currently being achieved can be assessed in the review of new drug discovery by Williams and Duncan. On the other hand, the molecular typing of strains of tubercle bacillus has developed directly and rapidly out of basic studies and has filled a glaring gap in the TB control toolbox, as reviewed by Behr and Mostowy. The immunology of tuberculosis is proving slow to yield its secrets and undergo paradigm shifts. Accordingly, there is a lack or immune correlates of protection that can be applied to people to predict either the outcome of infection or the effect of vaccination and this unsatisfactory situation is surveyed by Fletcher; clinical evaluation of new vaccines could be severely delayed if adequate correlates are not found soon.Support for a hypothesis relating excessive type 2 (Th2) immune responses to failure of immunity through inadequate bactericidal and cytotoxic T cell responses is drawn together by Rook. In relation to vaccine composition, insight into the role and potential utility of bacterial heat shock proteins as antigens and adjuvants in immunity is reviewed by Walker et al. The thrust for new fully defined and synthetic vaccines to complement or replace the live BCG vaccine is epitomised by the work reviewed by McMurry et al. and efforts to refine and enhance BCG itself by genetic engineering are reviewed by Hernandez-Pando et al. Although the potential of immunotherapy as an adjunct to chemotherapy has been largely ignored until now, encouraging indications of what might be achievable have been obtained in mice and the current position is summarised by Roy et al..........