ReviewImmunology of tuberculosis and implications in vaccine development
Introduction
Mycobacterium tuberculosis is an acid-fast bacillus that grows very slowly. Humans are the natural host for this pathogen, which is transmitted via the respiratory route. There are ∼8 million new cases of tuberculosis worldwide and at least 1.5 million deaths per year. Although the disease can be controlled by antibiotic treatment, the course of treatment is lengthy and involves two to four specific antimycobacterial drugs. In many parts of the world, access to the drugs is limited, and compliance with the drug regimen is often poor. Although drug treatment can be very effective, a vaccine that prevents infection and/or disease will be necessary to control or eliminate tuberculosis worldwide. Unfortunately, an effective vaccine against tuberculosis has not been developed. Most of the world's population is vaccinated with BCG, an attenuated M. bovis strain, at birth, and often boosted with BCG during childhood. Although BCG can be effective in reducing the incidence of childhood tuberculosis, particularly meningitis, it is relatively ineffective in protecting against adult tuberculosis, and does not prevent infection with the organism. Thus, BCG-immunized persons still become infected with M. tuberculosis, can develop active tuberculosis, and can harbor the organism and reactivate later in life. The efficacy of BCG in human trials has varied from 0% to 80%. It should be stressed that although the majority of the world's population is BCG vaccinated, the incidence of tuberculosis is still staggering. Clearly, a more effective vaccine against this disease is needed.
The course of M. tuberculosis infection in humans is unusual for bacterial pathogens. Following infection, a small percentage of people progress to primary tuberculosis (within 1–2 years), while most control the infection leading to a clinically latent infection. This latent infection can be maintained for the lifetime of the host with no clinical symptoms and no obvious adverse effects. The reactivation of latent infection occurs in 5–10% of infected persons, and can be triggered by immunosuppression due to age, corticosteroids, malnutrition, infection with the human immunodeficiency virus (HIV), or other factors. The course of disease is heavily influenced by the immune response mounted against M. tuberculosis. Persons who are immunocompromised, including HIV+ persons, have a much higher risk of developing active tuberculosis following infection.1
The immune response mounted against M. tuberculosis is multifaceted and complex. The organism multiplies after infecting a host's lungs, probably within alveolar macrophages. The effective innate immune responses to M. tuberculosis are largely unknown, but clearly important, since a subset of people exposed to M. tuberculosis do not become infected (as measured by tuberculin skin test reactivity). Shortly after infection, an adaptive immune response is generated. Data from humans and animal models have indicated that CD4 and CD8 T cells are activated in response to M. tuberculosis infection. There is also a strong antibody response generated in infected hosts, although the contribution of B cells or antibodies to control of infection remains controversial. Cytokines produced by T cells contribute in a multitude of ways, including by the activation of macrophages, the host cell in which M. tuberculosis primarily resides. CD8 T cells can also be cytotoxic for infected cells. The infection is chronic and stimulates formation of granulomas in the lungs. These granulomas consist of lymphocytes (CD4 and CD8 T cells, as well as B cells) surrounding macrophages, some of which contain M. tuberculosis. In addition, fibroblasts and other cells can be present within the granuloma. The granuloma serves to limit the spread of the infection by walling off the organisms from the rest of the lung, as well as providing a local environment for the action of the immune cells. On the other hand, M. tuberculosis has evolved strategies for persisting within the granuloma, and this environment may provide some level of protection for the bacteria. However, without granuloma formation, the bacteria are not contained and the infection quickly spreads to other organs. HIV+ persons who contract tuberculosis can be deficient in granuloma formation, and the infection is not well contained in these patients.
Section snippets
Vaccine strategies against
The development of an effective vaccine against tuberculosis is an enormously daunting task. This is due to a number of factors. One strategy for designing a vaccine involves identification of a protein produced by the bacterium that is essential for virulence. Neutralization of this protein by an immune response induced by vaccination should, in essence, disarm the pathogen and prevent it from causing disease. This is the principle behind certain vaccines currently used to prevent diseases
Macrophages
The macrophage is key to the control of M. tuberculosis infection. The organism can multiply within resting macrophages, but can be inhibited or killed when the macrophage is activated. Murine macrophages possess demonstrable antimycobacterial function in tissue culture systems.2., 3., 4. IFN-γ is the key activating agent that triggers these antimycobacterial effects.5., 6. Tumor necrosis factor-alpha (TNF-α), although ineffective when used alone, synergizes with IFN-γ to induce
Summary
The immune response to M. tuberculosis is complex and multifaceted. Many components of the immune response appear to be necessary or important in the protective response. These include CD4 and CD8T cells, cytokines such as IFN-γ and TNF-α, and macrophage activation. A clear understanding of the induction of these responses, as well as the precise role that each component plays in the protection is necessary in the ongoing research to develop an effective vaccine against the organism responsible
Acknowledgements
I am grateful to my longtime collaborator Dr. John Chan for discussions relevant to this review. In addition, I thank the members of my laboratory for their helpful comments and discussions. Finally, I am grateful to the National Institutes of Health (AI38411, AI37859, AI36990, AI47485) and American Lung Association for their support of my research.
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