Nature Medicine Special Web Focus: Tuberculosis (2000)
Tuberculosis: Not just a bad cough!
David G. Russell
College of Veterinary Medicine, Cornell University
Tuberculosis remains a disease that carries a social stigma because it maintains its tightest grip on populations that suffer from overcrowding, poor nutrition and poor housing. Nonetheless, as the US experienced during the recent upsurge in tuberculosis in American cities in the 1980s, the bacterium is obviously omnipresent and there are few barriers against broader spread in the population. It is generally accepted that Mycobacterium tuberculosis invaded the human population from cattle during the domestication of farm animals in the Fertile Crescent approximately 10,000–15,000 years ago. It is closely related to the causative agent of bovine tuberculosis, M. bovis, the parent of bacillus Calmette-Guérin (BCG), which is widely used as a vaccine against human tuberculosis. As bacterial pathogens go, M. tuberculosis has an enviable penetrance of its host population, and one-third of the world remains positive for the bacteria by skin testing. A positive skin test bears witness to exposure to the organism and is evidence of a previous or current infection. The ubiquitous presence of M. tuberculosis has had a fundamental effect on shaping human evolution and, like many microbial pathogens that were acquired from our livestock, these pathogens were chief agents of depopulation during colonization of the New World.
The course of infection Mycobacterium tuberculosis infections are acquired through inhalation of infective bacilli. Once in the lung, the bacteria are internalized by alveolar macrophages and set up infection foci in the tissue of the alveolar wall. These foci expand through bacterial growth and recruitment of macrophages and lymphocytes that build the granuloma that defines this infection. The granuloma seems to support limited bacterial growth and prevents metastasis of the infection. Nonetheless, the granuloma also protects the bacterium from the immune response and is probably responsible for the persistent or latent nature of the infection. Clinical disease develops when this immune-mediated constriction is abrogated through immune compromise. This is usually a consequence of old age, malnutrition or a concurrent infection with human immunodeficiency virus, but often occurs years after the primary infection. At this time, the granuloma caseates and spills its contents into the lungs, and is transmitted as an aerosol generated by coughing. Modern-day incubation vessels such as subway cars and airplanes prove particularly effective at ensuring that socioeconomic barriers to infection are breached with reasonable frequency.
To what does M. tuberculosis owe its success? The reason for the effectiveness of tuberculosis as a pathogen is complex, comprising a blend of preadaptations and acquired genetic traits. The lipid-rich cell wall is an excellent example of a structure evolved in a saprophytic ancestor that confers obvious advantages to a pathogen that uses aerosol transmission and would benefit from an innate resistance against digestion by host cell hydrolases and attack by host radicals. Recent advances in the sequencing of entire microbial genomes has shown that many bacteria, most notably the enteric fauna, have a 'cassette' approach to pathogenesis, and exchange entire sets of genes encoding complex secretory apparatuses and effector proteins that modulate host function. Analysis of the genome of M. tuberculosis indicates such events have been infrequent; mobile DNA seems to be restricted to open reading frames encoding translocases and a couple of prophage insertion sites. Therefore, most of the pathogenic characteristics in M. tuberculosis have evolved in a more linear or Darwinian way.
Parasitization by M. tuberculosis is subtle and insidious. The success or failure of the infection is determined at the level of the macrophage that acts as the host cell for the microbe. The bacterium enters its host macrophage by phagocytosis and, instead of being delivered to lysosomes and digested, the bacterium arrests the normal progression of its phagosome down the endosomal continuum. Electronmicrographs of M. tuberculosis in murine macrophages 7 days after infection show the bacterium’s ability to survive and replicate within vacuoles in the host cell. This vacuole retains a high pH, shows limited hydrolytic activity, intersects poorly with the host cell’s antigen-presentation pathway, and yet is still dynamic and has access to the cell’s early endosomal compartments and the nutrients therein. This modulation of the host cell does not impair its ability to function; however, certain properties such as the ability to induce or respond to an immune response are diminished by the infection. Moreover, the bacterium shows considerable plasticity and is able to switch its metabolism, exploiting different carbon sources that become available during the course of infection. The ability of the bacterium to regulate or respond to the intracellular environment has been the subject of many recent studies, although the bacterial products that influence this host interface remain elusive.
What obstacles stand in the way of disease control? The economic status of the 'reservoir' population places considerable constraints on the traditional, commerce-based approach to infectious disease treatment and prevention. On paper, vaccination is probably the more desirable approach because it is cheap to administer and involves limited contact with the patient population. However, vaccines are extremely expensive to develop and pharmaceutical companies are loathe to invest resources in the development of a vaccine that the target population could not afford and that would likely have limited patent protection. In addition, we already have a vaccine, BCG, although it is under constant criticism for its limited efficacy; this raises the question of what sort of vaccine we need. Can subunit vaccines generate a response that is sufficiently strong and broad, or do we need an attenuated M. tuberculosis? If we use the attenuated bacteria, how avirulent, and, in consequence, asymptomatic, can the attenuated bacterium be, yet still induce protective immunity? It may not be possible to realize a 'zero-risk' live vaccine against tuberculosis. Finally, because natural infections with M. tuberculosis result more often in latency rather than in sterile immunity, it is unclear how to promote protective immunity using an attenuated strain of M. tuberculosis.
Chemotherapy is a slightly more attractive option for the pharmaceutical industry because it affords a more long-term use of product. Nonetheless, anti-tuberculosis drugs are still viewed as a low priority for most companies. This attitude prevails despite the reports of drug resistance that come in from all areas in which tuberculosis is on the rise, and despite the absence of new drugs appearing on the market. Treatment is problematic because of the extended duration of compliance: 6–9 months of multiple antibiotic therapy for an active infection. This period is required because even 'sensitive' strains have an innate resistance to antibiotics, and it is difficult to maintain tissue levels of the drug sufficiently above the minimum inhibitory concentration even in the best of circumstances. The identification of new drug targets and the development of shorter treatment regimens are essential to the effective management of this disease.
Regardless of the avenue explored, our attitude toward tuberculosis must evolve a more global rather than national or commercial perspective. Smallpox was a more vulnerable microbe than tuberculosis because it did not cause latent infections, and protective immunity by vaccination was clearly obtainable; nonetheless, it was only eradicated when developed countries appreciated that improving the health of one’s weakest 'neighbor' was the best route to protection of one's own population. The 'leper colony approach' to infectious disease management has outlived its usefulness.
The articles in this issue of Nature Medicine explore these matters in greater depth and report on recent advances in both our understanding of the complex biology of this pathogen, and in our attempts to limit its spread within the human population.
David G. Russell, PhD
Microbiology and Immunology,
College of Veterinary Medicine,
Cornell University,
Ithaca, NY 14853
tel 607 253 3401
FAX 607 253 4058
E-mail dgr8@cornell.edu
