ReviewTumor necrosis factor alpha in mycobacterial infection
Introduction
Tuberculosis (TB) is a bacterial infectious disease which primarily affects the lung and causes a high death toll worldwide [1]. TB is caused by Mycobacterium tuberculosis (Mtb), a facultative intracellular bacterium which infects and persists in macrophages and other myeloid cells. Exposure to Mtb results in active TB in only 5–10% of infected individuals and the vast majority of the infected population develops a latent TB infection (LTBI), which can persist lifelong [2]. Upon failure of the immune response, e.g. due to co-infection with human immunodeficiency virus (HIV), LTBI cases are at high risk of developing active disease. Control of TB disease correlates with the development a T helper 1 (Th1) immune response, comprising interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α)-secreting lymphocytes, which induce antimycobacterial programs in infected macrophages. Mtb infection, disease progression and pathogen persistence are characterized by fine-tuned tissue accumulation of myeloid and lymphoid cells into highly organized structures, termed granulomas [3]. These tissue alterations, which represent hallmarks of TB, are primarily controlled by TNF-α. Thus, in TB, protection and pathology are modulated to a great extent by TNF-α. These aspects will be addressed in the following, emphasizing the key biological processes regulating cytokine availability, TNF-α-coordinated check-points for TB control and potential intervention strategies related to this cytokine.
Section snippets
Discovery of TNF-α: with a little help from mycobacteria
Mycobacteria and TNF have come a long way together. Both the discovery of lymphotoxin (LT; now termed TNF-β) and of TNF-α, critically involved mycobacteria. Nancy H. Ruddle and Byron H. Waksman [4], [5], [6] induced LT secretion in lymphocytes from mycobacteria-immune rats by restimulation with purified protein derivative (PPD) of mycobacteria. The team of Lloyd J. Old found that in vivo induction of TNF required priming with the TB vaccine bacille Calmette–Guérin (BCG) followed by challenge
Cellular sources and regulatory pathways for TNF-α production in TB
TNF-α is abundant at the site of bacterial persistence in pulmonary TB in patients [11], [12], [13], [14] and experimental models [15] indicating active cytokine stimulation. Various cell types are endowed with the propensity to produce TNF-α, yet mononuclear phagocytes represent the dominant cellular source of this cytokine in granulomatous diseases [16]. Early work has demonstrated that upon BCG encounter, and in particular, concurrent with IFN-γ stimulation [17], human macrophages release
TNF-α is a “dual function” cytokine
TNF-α is a pleiotropic cytokine with nonredundant roles in TB. Accordingly, perturbations of TNF-α levels significantly affect the course of infection. Experimental TB studies, as well as observations arising from clinical application of TNF-α blockers, added valuable information on how TNF-α contributes to TB disease pathogenesis. TNF-α elicits essential proinflammatory functions and low abundance or absence of this cytokine is associated with fatal TB progression. This detrimental outcome is
Lessons from anti-TNF-α therapy
The TNF signaling pathway proved amenable for intervention against autoimmune and chronic inflammatory diseases and TNF-α blockers are successfully integrated in therapy of such diseases, including rheumatoid arthritis (RA), Crohn's disease and psoriasis [73]. Clinical application of anti-TNF drugs have significantly contributed to a better understanding about the role of TNF-α in TB and verified the essentiality and sufficiency of this cytokine in containment of dormant Mtb within solid
Conclusions and perspectives
TB is an inflammatory disease and TNF-α is one of the critical proinflammatory cytokines governing TB pathogenesis. Available information supports a model in which TNF-α, when kept at bay, contains Mtb infection in solid granulomas. The appropriate concentration does not accomplish sterile bacterial eradication, but development of solid granulomas which contain Mtb with minimal collateral damage. An important task will be to minimize risk of TB reactivation post-treatment with TNF-α blockers,
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgements
We thank Mary Louise Grossman for excellent help in the preparation of this manuscript and Diane Schad for preparing the figures.
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