Review
Immunology of tuberculosis and implications in vaccine development

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Abstract

Mycobacterium tuberculosis is a very successful pathogen that can survive and persist in the human host in the face of a robust immune response. This immune response is sufficient to prevent disease in the majority of infected persons, providing compelling evidence that immunity to tuberculosis is possible. However, it is more striking that the strong immune response is not generally effective at eliminating the organisms, during either initial infection or the persistent or latent phase of infection. Studies in animal models and in humans have demonstrated the wide range of immune components involved in the effective response against M. tuberculosis. These components include T cells (both CD4+ and CD8+), cytokines, including IFN-γ, IL-12, TNF-α, and IL-6, and macrophages. The precise roles and functions of these cells and molecules (and others) are still being defined and may differ in acute and chronic infection. These immune responses are directed towards containing or eliminating the tubercle bacillus within the tissues of the host. The estimated eight million new cases of tuberculosis each year clearly demonstrate that these responses are not always effective. M. tuberculosis has obviously evolved a variety of mechanisms to evade destruction by the immune response. Studying both the host and the pathogen will elucidate potential vaccine candidates. In this review, the known functions of immune components in the response to M. tuberculosis and implications for vaccine development will be discussed.

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 M.tuberculosis

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.

References (92)

  • G.A.W. Rook et al.

    Activation of macrophages to inhibit proliferation of Mycobacterium tuberculosiscomparison of the effects of recombinant gamma interferon on human monocytes and murine peritoneal macrophages

    Immunology

    (1986)
  • I. Flesch et al.

    Mycobacterial growth inhibition by interferon-g activated bone marrow macrophages and differential susceptibility among strains of Mycobacterium tuberculosis

    J Immunol

    (1987)
  • I.E.A. Flesch et al.

    Activation of tuberculostatic macrophage functions by gamma interferon, interleukin-4, and tumor necrosis factor

    Infect Immun

    (1990)
  • A.H. Ding et al.

    Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages

    J Immunol

    (1988)
  • J. Chan et al.

    Effect of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis

    Infect Immun

    (1995)
  • J. MacMicking et al.

    Identification of nitric oxide synthase as a protective locus against tuberculosis

    Proc Natl Acad Sci USA

    (1997)
  • J.L. Flynn et al.

    Effects of aminoguanidine on latent murine tuberculosis

    J Immunol

    (1998)
  • C.A. Scanga et al.

    The NOS2 locus confers protection in mice against aerogenic challenge of both clinical and laboratory strains of Mycobacterium tuberculosis

    Infect Immun

    (2001)
  • T.H. Ottenhof et al.

    Novel human immunodeficiencies reveal the essential role of type-1 cytokines in immunity to intracellular bacteria

    Immunol Today

    (1998)
  • S. Nicholson et al.

    Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis

    J Exp Med

    (1996)
  • M. Bonecini-Almeida et al.

    Induction of in vitro human macrophage anti-Mycobacterium tuberculosis activityrequirement for IFN-gamma and primed lymphocytes

    J Immunol

    (1998)
  • K. Rockett et al.

    1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line

    Infect Immun

    (1998)
  • C-.H. Wang et al.

    Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages

    Eur Respir J

    (1998)
  • J.D. McKinney et al.

    Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase

    Nature

    (2000)
  • J. Armstrong et al.

    Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes

    J Exp Med

    (1971)
  • P.D. Hart et al.

    Ultrastructural study of the behavior of macrophages toward parasitic mycobacteria

    Infect Immun

    (1972)
  • S. Sturgill-Koszycki et al.

    Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase

    Science

    (1994)
  • R.A. Henderson et al.

    Activation of human dendritic cells following infection with Mycobacterium tuberculosis

    J Immunol

    (1997)
  • C.H. Ladel et al.

    Interleukin-12 secretion by Mycobacterium tuberculosis-infected macrophages

    Infect Immun

    (1997)
  • K. Sano et al.

    Ovalbumin (OVA) and Myocbacterium tuberculosis bacilli cooperatively polarize anti-OVA T-helper cells foward a Th1-dominant phenotype and ameliorate murine tracheal eosinophilia

    Am J Resp Cell Mol Biol

    (1999)
  • J.L. Flynn et al.

    IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection

    J Immunol

    (1995)
  • A.M. Cooper et al.

    Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis

    J Exp Med

    (1997)
  • D.B. Lowrie et al.

    Therapy of tuberculosis in mice by DNA vaccination

    Nature

    (1999)
  • I. Orme et al.

    T Lymphocytes mediating protection and cellular cytolysis during the course of Mycobacterium tuberculosis infection

    J Immunol

    (1992)
  • P.F. Barnes et al.

    Patterns of cytokine production by Mycobacterium-reactive human T-cell clones

    Infect Immun

    (1993)
  • I.M. Orme et al.

    Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection

    J Immunol

    (1993)
  • A. Lalvani et al.

    Human cytolytic and interferon gamma-secreting CD8+ T lymphocytes specific for Mycobacterium tuberculosis

    Proc Natl Acad Sci USA

    (1998)
  • I. Lyadova et al.

    An ex vivo study of T lymphocytes recovered from the lungs of I/St mice infected with and susceptible to Mycobacterium tuberculosis

    Infect Immun

    (1998)
  • N.V. Serbina et al.

    Early emergence of CD8+ T cells primed for production of Type 1 cytokines in the lungs of Mycobacterium tuberculosis-infected mice

    Infect Immunology

    (1999)
  • A.M. Cooper et al.

    Disseminated tuberculosis in IFN-γ gene-disrupted mice

    J Exp Med

    (1993)
  • J.L. Flynn et al.

    An essential role for interferon-γ in resistance to Mycobacterium tuberculosis infection

    J Exp Med

    (1993)
  • D.K. Dalton et al.

    Multiple defects of immune cell function in mice with disrupted interferon-gamma genes

    Science

    (1993)
  • M. Zhang et al.

    T cell cytokine responses in human infection with Mycobacterium tuberculosis

    Infect Immun

    (1995)
  • Y. Lin et al.

    Absence of a prominent TH2 cytokine response in human tuberculosis

    Infect Immun

    (1996)
  • L.M. Ting et al.

    Mycobacterium tuberculosis inhibits IFN-gamma transcriptional responses without inhibiting activation of STAT1

    J Immunol

    (1999)
  • A.G.D. Bean et al.

    Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin

    J Immunol

    (1999)
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