Tumor necrosis factor alpha in mycobacterial infection

doi:10.1016/j.smim.2014.04.003

Seminars in Immunology

Volume 26, Issue 3, June 2014, Pages 203-209

https://doi.org/10.1016/j.smim.2014.04.003 Get rights and content

Highlights

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In TB, TNF-α is produced primarily by myeloid cells and also by lymphocytes and its availability is regulated by cytokines, enzymes, lipid mediators and miRNAs.
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Local gradients dictate the detrimental or beneficial role of TNF-α by fine-tuning antibacterial capacities and tissue damage.
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Treatment with TNF-α blockers results in TB reactivation.
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Challenges ahead are to uncover networks governing TNF-α availability and cross-regulatory interactions between TNF-α and other immune or nonimmune mediators.

Abstract

Tumor necrosis factor alpha (TNF-α) is a critical immune mediator in protection against and pathology of tuberculosis (TB). TNF-α had been found to be associated with TB when it was originally identified as cachexin and until today TB research continues to unveil novel roles of this cytokine of highest relevance for the disease process and for novel intervention strategies. The essentiality of TNF-α for containment of active TB is reflected by redundancy of cellular sources of this cytokine, by complexity of mechanisms regulating TNF-α abundance and by substantial polyfunctionality of this mediator. The propensity of TNF-α to modulate granuloma biogenesis and integrity in TB represents the quintessential process in infection outcome. The TNF-α signaling pathway has proved amenable for therapy of autoimmune and other chronic inflammatory noninfectious diseases. Whether or not, and to which extent, host-directed therapies based on this cytokine will reach the patient as adjunct therapy against TB remains to be seen.

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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View full text

ReviewTumor necrosis factor alpha in mycobacterial infection

Highlights

Abstract

Introduction

Section snippets

Discovery of TNF-α: with a little help from mycobacteria

Cellular sources and regulatory pathways for TNF-α production in TB

TNF-α is a “dual function” cytokine

Lessons from anti-TNF-α therapy

Conclusions and perspectives

Conflict of interest statement

Acknowledgements

Pharmacol Ther

Immunity

Cell

Microb Pathog

Chest

Microbes Infect

Immunity

Cell

Immunity

Lancet Infect Dis

Immunity

Cell Host Microbe

Cell

Cell

Cell

J Theor Biol

Cytokine Growth Factor Rev

Lancet Infect Dis

Global tuberculosis report 2013

The immunological life cycle of tuberculosis

Nat Rev Immunol

Revisiting the role of the granuloma in tuberculosis

Nat Rev Immunol

Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. III. Analysis of mechanism

J Exp Med

Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. II. Correlation of the in vitro response with skin reactivity

J Exp Med

Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. I. Characterization of the phenomenon

J Exp Med

An endotoxin-induced serum factor that causes necrosis of tumors

Proc Natl Acad Sci U S A

A half century's progress against tuberculosis in New York city: 1900–1950

From bacteriology to immunology: the dualism of specificity

Nat Immunol

Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis

J Immunol

Cytokine production at the site of disease in human tuberculosis

Infect Immun

Cytokine levels correlate with a radiologic score in active pulmonary tuberculosis

Am J Respir Crit Care Med

Increased release of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis

Am J Respir Crit Care Med

The immune response in tuberculosis

Annu Rev Immunol

The pathophysiology of tumor necrosis factors

Annu Rev Immunol

The role of gamma-interferon, vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis

Immunology

Expression of tumor necrosis factor in vitro by human mononuclear phagocytes stimulated with whole Mycobacterium bovis BCG and mycobacterial antigens

Infect Immun

Activation of human dendritic cells following infection with Mycobacterium tuberculosis

J Immunol

Bacillus Calmette–Guerin mycobacteria stimulate human blood dendritic cells

Int J Cancer

Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88

J Clin Invest

The adaptor molecule CARD9 is essential for tuberculosis control

J Exp Med

Granzyme A produced by gamma(9)delta(2) T cells induces human macrophages to inhibit growth of an intracellular pathogen

PLoS Pathog

Increased mitogen-activated protein kinase activity and TNF-alpha production associated with Mycobacterium smegmatis- but not Mycobacterium avium-infected macrophages requires prolonged stimulation of the calmodulin/calmodulin kinase and cyclic AMP/protein kinase A pathways

J Immunol

Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b

Proc Natl Acad Sci U S A

Difference in neutrophil cytokine production induced by pathogenic and non-pathogenic mycobacteria

APMIS

Dominant TNF-alpha+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease

Nat Med

Review
Tumor necrosis factor alpha in mycobacterial infection