Mycobacterial pathogenesis: a historical perspective

Tuberculosis is an age-old human affliction which continues to flourish worldwide despite the development of effective drugs for its treatment and a vaccine (BCG) for its prevention. At least 8 million people die from this disease each year, a figure which is likely to increase as the AIDS epidemic continues its relentless spread into Africa and Southeast Asia. Consumption was shown to be caused by Mycobacterium tuberculosis more than a century ago, yet we still know very little about the mechanisms used by this organism to elude the normally effective cellular host defenses as it establishes a progressive infection within the lung. The majority of individuals exposed to tuberculous infection are able to limit the primary infection to the lungs and its lymph nodes, resulting in a latent form of the disease which can provide the host with a lifelong immunity to reinfection. While a great deal is known about the cellular mediators of this immune response (together with the cytokines which modulate them) we lack a clear understanding of the role that they play during the establishment of the dormant form of the disease. Live BCG vaccine has been widely used in many Third World countries as a major component of their tuberculosis control programs. However, several carefully controlled human trials have shown little protection achieved in vaccinated individuals. Development of improved vaccines, both for the prevention and therapy of this disease is an urgent research priority and a number of potential immunogens are under active investigation. However, our limited understanding of the pathogenesis of this chronic disease, together with a lack of data on the role played by different bacterial components in the modulation of the immune response, continues to severely limit our ability to develop a rational approach to this project. To achieve this goal, it will be necessary to establish innovative approaches to the presentation of protective antigens by taking advantage of recent advances in the molecular biology of this complex and enigmatic group of organisms.