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Review

Tumor necrosis factor alpha in mycobacterial infection Anca Dorhoi ∗ , Stefan H.E. Kaufmann ∗ Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany

a r t i c l e

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Keywords: Mycobacterium tuberculosis Inflammation Granuloma Cell death Immunotherapy

a b s t r a c t Tumor necrosis factor alpha (TNF-␣) is a critical immune mediator in protection against and pathology of tuberculosis (TB). TNF-␣ 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-␣ for containment of active TB is reflected by redundancy of cellular sources of this cytokine, by complexity of mechanisms regulating TNF-␣ abundance and by substantial polyfunctionality of this mediator. The propensity of TNF-␣ to modulate granuloma biogenesis and integrity in TB represents the quintessential process in infection outcome. The TNF-␣ 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. © 2014 Elsevier Ltd. All rights reserved.

1. 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-␥) and tumor necrosis factor-alpha (TNF-␣)-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-␣. Thus, in TB, protection and pathology are modulated to a great extent by TNF-␣. These aspects will be addressed in the following, emphasizing the key biological processes regulating cytokine availability, TNF-␣-coordinated check-points for TB control and potential intervention strategies related to this cytokine. 2. Discovery of TNF-␣: with a little help from mycobacteria

Abbreviations: AIDS, acquired immunodeficiency syndrome; ASK1, apoptosis signal-regulating kinase 1; BCG, bacille Calmette–Guérin; CARD, caspase recruitment domain; FADD, Fas-associated protein with death domain; ␥␦, gammadelta; HDT, host-directed therapy; HIV, human immunodeficiency virus; IFN, interferon; IL, interleukin; LT, lymphotoxin; LTBI, a latent TB infection; MK2, MAPK-activated protein 2; Mtb, Mycobacterium tuberculosis; MyD88, myeloid differentiation primary response gene 88; NK T cell, natural killer T cell; NOD, nucleotide-binding oligomerization domain; PMN, polymorphonuclear neutrophil; PPD, purified protein derivative; RA, rheumatoid arthritis; RIP, receptor-interacting serine/threonine-protein; ROS, reactive oxygen species; TB, tuberculosis; Th1, T helper 1; TLR, toll-like receptor; TNF, tumor necrosis factor; TNFR1, TNF receptor 1. ∗ Corresponding authors at: Max Planck Institute for Infection Biology, Department of Immunology, Charitéplatz 1, 10117 Berlin, Germany. Tel.: +49 30 28460 500/502; fax: +49 30 28460 501. E-mail addresses: [email protected] (A. Dorhoi), [email protected] (S.H.E. Kaufmann).

Mycobacteria and TNF have come a long way together. Both the discovery of lymphotoxin (LT; now termed TNF-␤) and of TNF␣, critically involved mycobacteria. Nancy H. Ruddle and Byron H. Waksman [4–6] 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 with endotoxin [7]. Even before this, the original description of tumor treatment by immunomodulation documented confounding effects of TB [8]. At the end of the 19th century, William B. Coley started therapy of sarcoma patients with bacterial vaccines. He combined Gram-positive and Gram-negative bacteria (streptococci, bacilli and serratiae) into Coley’s heat-killed toxin or Coley’s vaccine. Later studies showed

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that this vaccine did not act on the sarcomas directly, but indirectly, by inducing a combination of cytokines, including the macrophage products TNF-␣ and interleukin (IL)-1. Since streptococci also comprise superantigens, a contribution of the T cell cytokines LT and IFN-␥ is most likely. During the course of his studies, Coley observed that the efficacy of immunomodulation with his vaccine declined over the years. This was most likely due to decreasing incidences of TB in adults in New York city from ca. 500/100,000 in the early 20th century by 2–3-fold in the 1930s [9]. Because only 5–10% of Mtb-infected individuals develop TB during their lifetime, prevalence of Mtb infection must have been much higher, approaching 100% in the adult population in the late 19th century [10]. The most likely explanation is that LTBI – and even more so active TB – modulated cytokine responses to challenge with Coley’s vaccine. Vaccination with BCG was never introduced in the US, which could have caused a similar effect. Indeed, in experimental animal studies, Mtb infection and BCG vaccination were shown to increase sensitivity to Gram-negative bacteria by several investigators, including the above-mentioned team of Lloyd J. Old [7,8].

3. Cellular sources and regulatory pathways for TNF-␣ production in TB TNF-␣ is abundant at the site of bacterial persistence in pulmonary TB in patients [11–14] and experimental models [15] indicating active cytokine stimulation. Various cell types are endowed with the propensity to produce TNF-␣, 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-␥ stimulation [17], human macrophages release TNF-␣ [18]. Similarly, dendritic cells synthesize this cytokine in response to mycobacterial infection [19–21]. Multiple pathogen recognition receptors have been implicated in Mtb sensing and subsequent TNF-␣ release, including toll-like receptors (TLR), C-type lectins and nucleotidebinding oligomerization domain (NOD)-like receptors, along with downstream adaptor molecules, such as myeloid differentiation primary response gene 88 (MyD88) [22] and caspase recruitment domain (CARD)9 [23]. The numerous sensors and pathways converging to TNF-␣ production imply redundancy in innate immune mechanisms controlling TNF-␣ availability. Ancillary TNF-␣ regulatory networks have likely evolved as a consequence of the dominant role of this cytokine in infection control (see below) and have been shaped by the structural complexity of Mtb. Besides induction through pathogen sensing, TNF-␣ secretion is modulated in macrophages by cytokines, such as IFN-␥, enzymes and lipid mediators (Fig. 1). Granzyme A, involved in target cell lysis when produced by activated gamma-delta (␥␦) T cells, instructs macrophages to release TNF-␣ [24]. Leukotrienes modulate TNF␣ abundance in an autocrine manner: lipoxin A4 limits TNF-␣ production in macrophages, while leukotriene B4 exerts opposing effects [25]. Notably, nonpathogenic mycobacteria induce higher concentration of TNF-␣ than pathogenic strains [26,27] suggesting counter-regulation of this cytokine in myeloid cells during TB for the benefit of the pathogen. Recent studies have implicated small noncoding RNAs as limiting factors for TNF␣ release during Mtb infection [28] (Fig. 1). Lipomannans from virulent mycobacteria bind TLR-2, activate MAPK-activated protein 2 (MK2) and subsequently induce the micro-RNA 125b to confine TNF-␣ post-transcriptionally. Infection of human polymorphonuclear neutrophils (PMNs) with mycobacteria likewise results in TNF-␣ release and similar to mononuclear cells elevated cytokine abundance has been observed for nonvirulent strains [29]. Mononuclear phagocytes, including macrophages, inflammatory monocytes, foamy and multinucleated giant cells, are the main cells

Fig. 1. Production of TNF-␣ during TB. Mtb sensing by myeloid cells through membrane-bound or cytosolic pattern recognition receptors induces signaling events which initiate transcription and subsequent production of TNF-␣. Mtb components, such as lipomannans, interfere post-transcriptionally with TNF-␣ synthesis, by inducing miR-125b to destabilize TNF-␣ transcripts. In addition, distinct classes of eicosanoids differentially modulate TNF-␣ release, LXA4 limits and LTB4 fosters cytokine production, while enzymes and cytokines, such as granzyme, CD4 and CD8 T- lymphocytes, along with NKT cells and ␥␦ T-cells release TNF-␣ during TB. Abbreviations: CD1: CD1-restricted T cell; IFN-␥: interferon gamma; LM: lipomannan; LTB4: leukotriene B4; LXA4: lipoxin A4; miR: microRNA; MR1: MR1-restricted mucosa-associated invariant T cells; mRNA: messenger RNA; Mtb:Mycobacterium tuberculosis; NKT: natural killer T cell; PRR: pattern recognition receptor; TB: tuberculosis; TNF-␣: tumor necrosis factor alpha.

interacting with mycobacteria and harboring bacilli within tissue lesions, yet during active TB PMNs are present at the site of inflammation, containing Mtb [30] and thus contributing to local TNF-␣ availability. The subcellular events controlling TNF-␣ production by PMNs in TB await clarification. In addition to myeloid cells, T-lymphocytes represent a considerable source of TNF-␣ in TB. Both CD4 and CD8 T-cell subsets respond to TNF-␣ and produce this cytokine to further modulate phagocyte functions. Th1 polarization generally confers upon CD4+ T cells the propensity to release TNF-␣ often together with IFN-␥. Percentages of Mtb-specific TNF-␣-producing single CD4+ T lymphocytes apparently correlate with disease status and have been proposed as rapid diagnostic tool, allowing differentiation of LTBI from active TB cases [31]. Besides conventional CD4 and CD8 T cells, CD1-restricted T cells, natural killer T (NKT) cells and ␥␦ T cells [32–35] and more recently MR1-dependent Mtb-reactive mucosa-associated invariant T cells [36] have been also reported to contribute to TNF-␣ production in TB (Fig. 1). 4. TNF-␣ is a “dual function” cytokine TNF-␣ is a pleiotropic cytokine with nonredundant roles in TB. Accordingly, perturbations of TNF-␣ levels significantly affect the course of infection. Experimental TB studies, as well as observations arising from clinical application of TNF-␣ blockers, added valuable information on how TNF-␣ contributes to TB disease pathogenesis.

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TNF-␣ elicits essential proinflammatory functions and low abundance or absence of this cytokine is associated with fatal TB progression. This detrimental outcome is primarily a consequence of reduced antimycobacterial macrophage responses concurrent with impaired granuloma functionality. Yet, excessive TNF-␣ promotes immunopathology by interfering with cell death processes and induction of a hyper-inflammatory milieu. The relative abundance of TNF-␣ at particular stages of Mtb infection determines whether this cytokine is protective or deleterious. Thus, TNF-␣ emerges as “dual function” cytokine in TB. The antimicrobial functions of TNF-␣ have been described in murine models early after identification of this cytokine [37,38] and in murine macrophages challenged with Mtb [39,40]. These effects, which synergize with IFN-␥, have been reproduced with M. avium in human phagocytes [41], but not with Mtb [42,43], perhaps reflecting differential intrinsic killing modalities of macrophages between rodents and humans. Tissue requirements for TNF-␣ have been unequivocally linked to granuloma biogenesis and integrity (Box and Fig. 2). Susceptibility to TB of mice mutants lacking the TNF receptor 1 (TNFR1) or TNF-␣ has been correlated with the formation of defective granulomas [44,45]. Similar results have been recorded for animals receiving anti-TNF-␣ therapy during BCG or Mtb infection [38,46,47]. Poor phagocyte activation, reduced chemokine expression and defective granuloma organization cumulatively contribute to lethality of TNF-␣-deficient mice [48]. The essentiality of TNF-␣ for control of primary progressive TB has been extended to disease reactivation in humans with LTBI by numerous clinical trials with TNF-␣ inhibitors (see for review [49]) and TB studies in nonhuman primates [50]. Murine studies showing spontaneous reactivation in TNF-␣-deficient mice have recapitulated this finding [51]. Intravital microscopy revealed that TNF-␣ neutralization modifies not only granuloma size, but also the cellular composition within the tissue infiltrates by limiting the pool of noninfected macrophages [46]. Reciprocally, challenging mice with TNF-␣-expressing BCG has resulted in smaller lesions and well-defined granulomas [52]. In a mouse model which mimics human granulomas, solid granulomas become necrotic and then liquefy as a consequence of TNF-␣ neutralization [53]. Based on studies with M. marinum, a close relative of Mtb, and its natural host zebrafish, TNF-␣ has been implicated in granuloma maintenance rather than formation in this model system [54]. Direct antimicrobial effects concurrent with modulation of macrophage necrosis contributed to disease progression in zebrafish devoid of TNF-␣ signaling. Using various models, experimental TB has provided unequivocal evidence that TNF-␣ governs multiple aspects of granuloma biology and hence controls the hallmark tissue response in TB (Box and Fig. 2). TNF-␣ has been initially reported to regulate apoptosis by recruiting Fas-associated protein with death domain (FADD) to the TNFR signaling complex and subsequently activating caspase-8/10 pathways [16]. Apart from the FADD pathway, TNF-␣ activates kinases such as apoptosis signal-regulating kinase 1 (ASK1), p38 and c-Abl in TB leading to phosphorylation of FLIP(S) and subsequently interaction with the ubiquitin ligase c-Cbl to induce proteasomal degradation of FLIP(S) and caspase-8-induced apoptosis [55]. In different systems apoptosis results in divergent infection outcomes. Apoptosis limits bacterial replication independent of IFN-␥ in human macrophages [56], it restricts pulmonary TB in mice [57], yet fosters bacterial spread and progression of infection in the zebrafish [58]. Further studies suggest that virulent Mtb evade apoptosis [56,59]. In addition to inducing lower levels of TNF-␣ as compared to avirulent strains [26,27], virulent Mtb fosters TNFR2 shedding and necrotic cell death (see for review [60]). TNF-␣-induced apoptotic cell death of mycobacteria-infected human alveolar macrophages has been reported [61]. Apoptosis of infected cells was also described for mouse macrophages

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and zebrafish cells [57,58]. Apoptosis and necrosis are not mutually exclusive and may occur simultaneously at discrete ratios in populations of Mtb-infected macrophages. More recently, TNF␣ was shown to promote a programmed, highly inflammatory form of necrosis, namely necroptosis, in absence of FADD/caspase8 [62]. This mechanism has been described in mycobacterial infection in the zebrafish model [63]. Excessive TNF-␣ activates receptor-interacting serine/threonine-protein (RIP)1/3 kinases and mitochondrial reactive oxygen species (ROS) synthesis, necrosis of infected macrophages and transition into hyperinflammation. As a corollary, TNF-␣ induces various cell death patterns affecting bacterial containment at and cell recruitment to sites of infection and inflammation. Duality of TNF-␣ in conferring protection or pathology is principally determined by cytokine concentrations, yet interference with additional signaling pathways deserves consideration. Sufficient TNF-␣ amounts confer adequate responses limiting bacterial burdens, while excessive levels induce pathology in addition [25,52,63,64]. Hypervirulent Mtb strains curtail appropriate TNF-␣ secretion, among other Th1 type immune mediators, prompting progression to fatal disease [65]. Mutation in the TNF-␣ leader sequence resulting in elevated secretion of soluble TNF-␣ and excessive inflammation has been associated with the heightened lethality of I/St mice following Mtb infection [66]. Inoculation of a high dose of BCG-expressing TNF-␣ has similarly resulted in exacerbated inflammation in spite of restricted bacterial replication [52]. Work in the zebrafish model further established a connection between TNF-␣, leukotriene metabolism and tissue hyperinflammation [25,63]. As detailed above, tractable animal models have allowed correlations between local TNF-␣ levels, disease score, bactericidal activity and pathology. However, precise description of networks at molecular, cellular and tissue levels are scarce. More recently, efforts have been undertaken to model these processes in silico. Computational models are particularly relevant because in human TB, access to informative samples is limited and noninvasive procedures are impractical. Accordingly, results and the interpretation of TNF-␣ abundance and clinical TB disease are controversial. Some studies have reported selective increase of TNF-␣ plasma concentration initially post-chemotherapy concurrent with clinical deterioration [67]. Others have described reduced ex vivo monocyte-derived TNF-␣ in patients dying of TB or suffering of significant clinical deterioration [68]. Multiscale computational modeling of mature granulomas predicts that dynamics of TNF␣ and TNFR binding and trafficking directly affects inflammation level and Mtb growth [69]. The kinetics of TNFR1 internalization have been proposed to control infection within granulomas by dictating bacillary clearance versus excessive inflammation. It has been concluded that this process regulates autocrine and paracrine TNF-␣-induced responses. Accordingly, receptor internalization appears to favor activation of infected macrophages by reducing diffusion of the cytokine and to promote excessive inflammation by activating resting macrophages. As a consequence, the model proposes that by means of TNFR1 internalization, balanced autocrine/paracrine effects can be reached, which ideally confer efficient Mtb growth inhibition with minimal side effects. In addition, TNF-␣-dependent cell death, including apoptosis, impacts on inflammation and mycobacterial clearance. Multiple TNF-␣ activities balance macrophage recruitment and activation concurrent with Mtb growth control inside the granuloma [70,71]. More recently, IL-10 has been integrated in the computational model to analyze interactions between TNF-␣ and IL-10 [72]. Spatial localization of TNF-␣ and IL-10 within granulomas fine-tune bactericidal effects and tissue damage. Integration of additional factors into the multiscale computational modeling will certainly provide novel hypotheses for experimental verification. TNF-␣ likely represents a central hub of the antimycobacterial molecular interaction

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Box Tuberculosis (TB) is primarily a disease of the lung, which serves as major port of entry for the pathogen, Mycobacterium tuberculosis (Mtb), and primary site of disease manifestation. Granulomas are composed of hematopoietic cells, notably mononuclear phagocytes at different stages of maturation, dendritic cells as well as T and B lymphocytes. The mononuclear phagocytes comprise inflammatory monocytes, tissue macrophages and transformed macrophages such as foamy and multi-nucleated giant cells. As already noted by E. Metchnikov [95], monocytes and macrophages can kill or at least control growth of Mtb, whereas multi-nucleated giant cells primarily serve as habitat of Mtb. In humans, three distinct types of granulomas can be distinguished, which correlate with defined stages of infection and disease [96]. During latent Mtb infection, solid granulomas contain Mtb in a dormant stage. Dormancy of Mtb is characterized by low replicative and metabolic activity and is the characteristic feature of latent TB infection (LTBI) as it occurs in infected healthy individuals who control Mtb. Reactivation of active TB parallels transition into a necrotic granuloma, where Mtb transforms into a metabolically active highly replicative microorganism. These necrotic granulomas expand and cause significant tissue damage. As disease progresses, necrotic detritus in the center of granulomas liquefies through the action of hydrolytic enzymes and caseous granulomas develop. The caseous detritus provides a fertile soil for Mtb which grows to excessive numbers in the order of > 1012 bacilli per lesion. In addition, caseous granulomas form large cavities and cause major tissue damage. Mtb gains access to alveoli and capillaries allowing dissemination to the environment and to other organs. While solid granulomas predominate in LTBI, different forms of granulomas coexist in patients with active TB. Although the most prevalent and most impressive forms in active TB are the necrotic and caseous granulomas, where Mtb flourishes, solid granulomas containing dormant Mtb are also present. This has major implications for TB therapy: so-called active Mtb, which replicate and actively metabolize, are vulnerable to current TB drugs; in contrast, dormant Mtb with highly reduced replication and metabolism are phenotypically resistant to these drugs. This disparate behavior is at least partially responsible for prolonged treatment time of TB. Once active Mtb have been killed by chemotherapy, dormant Mtb still persist. After resuscitation they become metabolically active and start replication rendering them susceptible to drug treatment [97]. However, they also initiate granuloma necrosis and caseation resulting in tissue damage. Granulomas of mice are generally less structured and do not segregate into distinct stages as human ones. However, some mouse models have been developed which mimic at least some stages of human granulomas [53,98]. Granulomas in the guinea pig have more resemblance to human granulomas than murine ones [99,100]. Since the guinea pig is extremely sensitive to TB, caseous granulomas rapidly develop in this species. Granulomas in zebrafish infected with M. marinum resemble human TB granulomas during early maturation and undergo necrosis [101]. Hence, in contrast to mammalian tuberculous granulomas adult zebrafish lesions contain limited numbers of lymphocytes. Experimental TB provided evidence that TNF-␣ is a key determinate of granuloma formation and integrity. Exuberant or insufficient concentration of this cytokine greatly affects granuloma features and subsequently disease progression or containment.

Fig. 2. (Left) Low levels of TNF-␣ result in impaired granuloma formation characterized by disorganized structure, caseation, impaired activation of macrophages and presence of numerous bacilli inside myeloid cells and within the necrotic core. (Center) Sufficient levels of TNF-␣ drive formation of well organized, solid granulomas, containing infected myeloid cells in various activation stages, transformed macrophages and numerous lymphocytes typically present at the rim of the granuloma. (Right) Exuberant levels of TNF-␣ induce overactivation of infected macrophages within well-defined granulomas, facilitate programmed necrosis of the infected cells, release of bacilli and their extracellular replication. TNF-␣ (arrow going down) = reduced local abundance of TNF-␣. TNF-␣ (balanced) = proper local abundance of TNF-␣. TNF-␣ (arrow going up) = heightened local abundance of TNF-␣.

network, which tips the balance to the benefit of the host or the mycobacterial pathogen. 5. Lessons from anti-TNF-␣ therapy The TNF signaling pathway proved amenable for intervention against autoimmune and chronic inflammatory diseases and TNF␣ 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-␣ in TB and verified the essentiality and sufficiency of this cytokine in containment of dormant Mtb within solid granulomas during LTBI. Therapy with infliximab, a chimeric monoclonal antibody against TNF-␣ resulted in TB reactivation in RA patients with LTBI [74], raising awareness about risk of TB as serious adverse

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event of the treatment. Multiple clinical studies have revealed that the risk to develop TB disease is highest during the first 6 months of therapy with TNF-␣ blockers [75]. Application of monoclonal antibodies or soluble TNFR both augmented occurrence of TB reactivation with a significantly higher risk being associated with anti-TNF-␣ antibodies [76]. These differential outcomes reflect different dosages, pharmacokinetics, TNF-␣ binding and stoichiometry, which impact on biological processes such as cytotoxicity, apoptosis, T-cell activation and cytokine expression [49]. Based on observations from clinical trials, initiation of anti-TNF treatment is currently preceded by screening for LTBI. Experimental studies revealed that TNF-␣ blockers primarily affect containment of dormant bacteria within solid granulomas and substantiated human epidemiologic observations that monoclonal antibodies rather than soluble TNFR affect granuloma architecture more severely [77]. Studies of LTBI in macaques showed that antiTNF-␣ agents initiate changes in the thoracic lymph nodes and cause a diverse spectrum of lesions, including extra-pulmonary sites [50]. In contrast to mouse studies, comparable granuloma structure and composition was observed in monkeys receiving anti-TNF-␣ blockers and animals developing primary progressive disease. Insights into intra-lesion changes are impracticable for human studies and therefore experimental TB has to provide information on alterations induced upon anti-TNF-␣ treatment. Investigations on activities of human peripheral blood cells have indicated that during TNF-␣ neutralization, responses and numbers of effector memory CD8 T-lymphocytes are diminished with negative impact on their antimicrobial capacities [78]. In certain cases withdrawal of TNF-␣ blockade can promote TB exacerbation in LTBI resulting in the life-threatening immune reconstitution inflammatory syndrome [79]. TNF-␣ blockers disturb multiple disease mechanisms and future studies will presumably uncover additional immune pathways and mediators affected by this immune therapeutic regime.

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for TB. Yet, increasing incidences of multi-, extensively [85] and even totally drug-resistant forms of TB [86], which evade canonical therapy, call for such novel approaches directed at host defense mechanisms. The hyperinflammation induced by exuberant TNF-␣ production may result, at least in part, from processes not yet investigated in TB. TNF-␣ and erythropoietin, a molecule controlling erythropoiesis and endowed with a tissue-protective function, counter-regulate each other [87]. Intriguingly, anemia is a hematologic disorder associated with TB and serum erythropoietin concentrations are reduced in TB [88]. Yet, to our knowledge, no study so far has attempted to elucidate the crosstalk between erythropoietin and TNF-␣. The CD68+ macrophages seem to produce erythropoietin in TB granulomas [89]. How erythropoietin/TNF-␣ crosstalk in TB and whether this is amenable to HDT (e.g. delivery of carbamyl-erythropoietin) could be an interesting line of investigation. In a similar vein, contribution of lung epithelia to the overall TNF-␣ response, including dysbalanced inflammation, awaits elucidation. TNF-␣ promotes release of chemokines and antimicrobials by pneumocytes during bacterial infections [90,91]. Hence, respiratory epithelia could contribute to recruitment of inflammatory cells into tissue and subsequently granuloma formation/integrity as well as in situ release of antimycobacterial peptides. Identification of leukotriene pathways which fine-tune TNF␣-driven inflammation has led to the rational design of genotype-directed therapies for successful TB disease cure [25,63]. Interestingly, reduction of TNF-␣ concentrations by adjunctive thalidomide therapy has improved clinical outcome in pulmonary TB [92], yet showed contradictory results for meningeal TB [93,94]. These findings indicate that this type of therapy may need to be host genotype-directed. Challenges ahead include elucidation of additional networks affecting TNF-␣ balance. Furthermore, coinfections such as acquired immunodeficiency syndrome (AIDS) or parasitic diseases are endemic in high-burden TB regions, and understanding how these conditions disturb TNF-␣ abundance, could provide guidance for more effective intervention measures against TB.

6. Conclusions and perspectives TB is an inflammatory disease and TNF-␣ is one of the critical proinflammatory cytokines governing TB pathogenesis. Available information supports a model in which TNF-␣, 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-␣ blockers, since this intervention remains beneficial for treatment of RA and other chronic inflammatory noninfectious conditions. Efforts to design agents that prevent LTBI progression to active TB disease leaving anti-inflammatory effects unaffected are being made. The observation that membrane TNF-␣ is sufficient for sustenance of LTBI [80] indicates that agents which exempt membrane TNF-␣ would be a viable option for treatment of RA patients. Reduction of TNF-␣ abundance at the affected sites (e.g. arthritic joints for RA patients) while maintaining sufficient cytokine concentration at solid granulomas containing dormant Mtb is also desirable. Modulation of TNF-␣ concentrations as host-directed therapy (HDT) is emerging as an adjunctive treatment to chemotherapy for TB [81–83]. The beneficial effects of HDT combined with drug treatment have been illustrated by accelerated Mtb clearance, reduced necrosis and faster resolution of lung lesions [84]. Whether or not, and to which extent, additional antagonistic cytokines such as IL-10, or synergistic cytokines such as IFN-␥, are involved, remains to be established. Elucidation of the consequences of TNF␣ neutralization in combination with conventional chemotherapy is compulsory prior to introduction of novel treatment regimens

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Please cite this article in press as: Dorhoi A, Kaufmann SHE. Tumor necrosis factor alpha in mycobacterial infection. Semin Immunol (2014), http://dx.doi.org/10.1016/j.smim.2014.04.003

Tumor necrosis factor alpha in mycobacterial infection.

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...
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