Search

Abstract: Tumor necrosis factor (TNF) is critical and non-redundant to control Mycobacterium tuberculosis infection and cannot be replaced by other proinflammatory cytokines. Overproduction of TNF may cause immunopathology, while TNF neutralization reactivates latent and chronic, controlled infection, which is relevant for the use of neutralizing TNF therapies in patients with rheumatoid arthritis. [Copyright &y& Elsevier]

Tuberculosis (TB) and malaria remain serious threats to global health. Bacillus Calmette‐Guerin (BCG), the only licensed vaccine against TB protects against severe disseminated forms of TB in infants but shows poor efficacy against pulmonary TB in adults. Co‐infections have been reported as one of the factors implicated in vaccine inefficacy. Given the geographical overlap of malaria and TB in areas where BCG vaccination is routinely administered, we hypothesized that virulence‐dependent co‐infection with Plasmodium species could alter the BCG‐specific immune responses thus resulting in failure to protect against Mycobacterium tuberculosis. We compared virulent Plasmodium berghei and non‐virulent Plasmodium chabaudi, their effects on B cells, effector and memory T cells, and the outcome on BCG‐induced efficacy against M. tuberculosis infection. We demonstrate that malaria co‐infection modulates both B‐ and T‐cell immune responses but does not significantly alter the ability of the BCG vaccine to inhibit the growth of M. tuberculosis irrespective of parasite virulence. This malaria‐driven immune regulation may have serious consequences in the early clinical trials of novel vaccines, which rely on vaccine‐specific T‐cell responses to screen novel vaccines for progression to the more costly vaccine efficacy trials. [ABSTRACT FROM AUTHOR]

The control of Mycobacterium tuberculosis infection depends on recognition of the pathogen and the activation of both the innate and adaptive immune responses. Toll-like receptors (TLR) were shown to play a critical role in the recognition of several pathogens. Mycobacterial antigens recognise distinct TLR resulting in rapid activation of cells of the innate immune system. Recent evidence from in vitro and in vivo investigations, summarised in this review demonstrates TLR-dependent activation of innate immune response, while the induction of adaptive immunity to mycobacteria may be TLR independent. [Copyright &y& Elsevier]

Tuberculosis presents a global health challenge, and tumour necrosis factor (TNF) signalling is required for host immunity against Mycobacterium tuberculosis (Mtb). TNF receptor shedding, however, compromises effective immunity by reducing bioactive TNF through the formation of inactive complexes. In this study, we first compared the effect of total soluble TNF receptors using a transgenic p55ΔNS/p75−/− murine strain on host protection during a low‐dose aerosol Mtb H37Rv challenge. We report that the presence of membrane‐bound TNFRp55 alone in the absence of TNFRp75 results in superior control of a primary Mtb infection where p55ΔNS/p75−/− hyperactive dendritic cells displayed an increased capacity to induce a hyperactive Mtb‐specific CD4+ T‐cell response. p55ΔNS/p75−/− dendritic cells expressed a higher frequency of MHCII and increased MFIs for both CD86 and MHCII, while CD4+ T cells had higher expression of CD44 and IFN‐γ. Next, the relative contributions of soluble TNFRp55 and soluble TNFRp75 to host protection against either primary Mtb infection or during reactivation of latent tuberculosis were delineated by comparing the experimental outcomes of control C57BL/6 mice to transgenic p55ΔNS/p75−/−, p55ΔNS and p75−/− mouse strains. We found that soluble TNFRp55 is redundant for immune regulation during the chronic stages of a primary Mtb infection. However, TNFRp55 together with soluble TNFRp75 has a crucial role in immune regulation of reactivation of latent tuberculosis. [ABSTRACT FROM AUTHOR]

Summary: TNF signalling through TNFRp55 and TNFRp75, and receptor shedding is important for immune activation and regulation. TNFRp75 deficiency leads to improved control of Mycobacterium tuberculosis (M. tuberculosis) infection, but the effects of early innate immune events in this process are unclear. We investigated the role of TNFRp75 on cell activation and apoptosis of alveolar macrophages and neutrophils during M. tuberculosis and M. bovis BCG infection. We found increased microbicidal activity against M. tuberculosis occurred independently of IFNy and NO generation, and displayed an inverse correlation with alveolar macrophages (AMs) apoptosis. Both M. tuberculosis and M. bovis BCG induced higher expression of MHC‐II in TNFRp75−/− AMs; however, M bovis BCG infection did not alter AM apoptosis in the absence of TNFRp75. Pulmonary concentrations of CCL2, CCL3 and IL‐1β were increased in TNFRp75−/− mice during M, bovis BCG infection, but had no effect on neutrophil responses. Thus, TNFRp75‐dependent regulation of mycobacterial replication is virulence dependent and occurs independently of early alveolar macrophage apoptosis and neutrophil responses. [ABSTRACT FROM AUTHOR]

Objective(s): This study aimed to explore the contribution of tumor necrosis factor (TNF) in the recruitment of B-cell and secretion of immunoglobulins (Igs) during cerebral tuberculosis (TB). Materials and Methods: In this work, the contributing role of TNF in regulating Ig secretions was investigated by comparing wild type TNF (TNFf/f), B-cell-derived TNF (BTNF-/-), and complete TNF ablation (TNF-/-) in a mouse cerebral Mycobacterium tuberculosis infection. Using flow cytometry and ELISA, we were able to examine the recruitment of B-cell subsets, and the production of Igs; also assessed the expression of surface markers on B cell subsets. Results: Here, we found that TNF-/- mice showed defective expression of IgA, IgG, and IgM antibodies compared with TNFf/f and BTNF-/- mice, which was significantly decreased in the expression of surface markers and co-stimulatory molecules. Moreover, mice that produced low antibody levels were not able to control infection, therefore progressed to disease; providing direct evidence for the TNF gene-regulating humoral immunity during central nervous system (CNS) M. tuberculosis infection. In contrast, BTNF-/- mice controlled the infection and had levels of IgA, IgG, and IgM comparable to TNFf/f mice. Conclusion: Together, our results demonstrate that TNF may serve as an essential regulator of antibody-mediated immune responses in CNS TB. However, the protective level exhibited by TNFproducing B cells could be defined as baseline protection that could be used in the development of new therapeutic targets or designing new vaccines. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a receptor mainly expressed on myeloid cells, and it plays an important role in modulating immune response against infectious agents. The function of TREM-1 on nonmyeloid cells such as Vϐ2 T cells has not been characterized and their role in pulmonary tuberculosis (TB) remains unclear. To assess the expression of TREM-1 on blood Vϐ2 T cells from pulmonary TB patients and investigate its mechanism of induction, we exploited flow cytometry analysis to study the expression of TREM-1 on Vϐ2 T cells from active pulmonary TB patients and control subjects. In this study we demonstrate that TREM-1 (TREM-1+) is highly expressed on Vd2 T cells of patients with active pulmonary TB. Unlike TREM-12-expressing Vϐ2 T cells, TREM-1+-producing Vϐ2 T cells display APC-like phenotypes. Surprisingly, TREM-1+ signaling promotes the Ag-presenting capability of Vϐ2 T cells to induce the CD4+ T cell response. TREM-1+Vϐ2 T cells induced the proliferation and differentiation of naive CD4+ T cells, as well as the elimination of intracellular mycobacteria. We identified TREM-1+ (but not TREM-12) as an Ag-presentation amplifier on human blood Vϐ2 T cells, and data shed new light on the regulation of V&ϐ#976;2 T cells in the phase of innate and adaptive immune responses against Mycobacterium tuberculosis infection. Targeting TREM-1+V2ϐ T cells may be a promising approach for TB therapy. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis can infect ‘non‐classical immune cells’, which comprise a significant constituency of cells that reside outside of those defined as ‘classical immune cells’ from myeloid or lymphoid origin. Here we address the influence of specific ‘non‐classical immune cells’ in host responses and their effects in controlling mycobacterial growth or enabling an environment conducive for bacilli persistence. The interaction of M. tuberculosis with epithelial cells, endothelial cells, fibroblasts, adipocytes, glia and neurons and downstream cellular responses that often dictate immune regulation and disease outcome are discussed. Functional integration and synergy between ‘classical’ and ‘non‐classical immune cells’ are highlighted as critical for determining optimal immune outcomes that favour the host. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. Methods: We generated neuron-specific TNF-deficient (NsTNF-/-) mice and compared outcomes of disease against TNFf/f control and global TNF-/- mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). Results: Intracerebral M. tuberculosis infection of TNF-/- mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF-/- mice were resistant to infection and presented with a phenotype similar to that in TNFf/f control mice. Impaired immunity in TNF-/- mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. Conclusion: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB. [ABSTRACT FROM AUTHOR]

Objectives Phenothiazines are a commercially available class of psychotropic drugs known to show antituberculosis activity. At clinically relevant bactericidal doses, however, the psychotropic drugs produce undesirable side effects in addition to their neuroleptic properties. This study aimed to evaluate rationally designed novel phenothiazines as antimycobacterial drug candidates. Methods Remodelling of psychotropic drugs by substitution of characteristic N-alkylamine side chains, important for CNS activity, with N-alkylsulphonates gave novel drug candidates, which were then tested for post-synaptic receptor binding affinity in a radioligand displacement assay. The bactericidal activities were screened using green fluorescent protein (GFP) microplate assays, and the efficacy of intracellular bacillus killing was evaluated by cfu enumeration. Results Of the four selected phenothiazine derivatives (PTZ3, PTZ4, PTZ31 and PTZ32) tested, PTZ31 displayed marginal serotonergic activity. The remaining three derivatives did not exhibit dopamine or serotonin receptor binding activity. In vitro results showed significant growth inhibition of virulent Mycobacterium tuberculosis with MICs of 12.5–25 mg/L. None of the phenothiazine derivatives displayed cytotoxicity in infected primary bone marrow-derived macrophages. Moreover, the phenothiazines showed significant antimycobacterial activity of between 40% and 60% against intracellular (ex vivo) M. tuberculosis. Conclusions We demonstrate that structural modification of the phenothiazine core is possible in a manner that does not affect the ability of the phenothiazine derivatives to inhibit M. tuberculosis, but that abolishes undesirable dopamine and serotonin receptor binding. [ABSTRACT FROM PUBLISHER]

Development of host protective immunity against Mycobacterium tuberculosis infection is critically dependent on the inflammatory cytokine TNF. TNF signals through 2 receptors, TNFRp55 and TNFRp75; however, the role of TNFRp75-dependent signaling in immune regulation is poorly defined. Here we found that mice lacking TNFRp75 exhibit greater control of M. tuberculosis infection compared with WT mice. TNFRp75-/- mice developed effective bactericidal granulomas and demonstrated increased pulmonary recruitment of activated DCs. Moreover, IL-12p40-dependent migration of DCs to lung draining LNs of infected TNFRp75-/- mice was substantially higher than that observed in WT M. tuberculosis--infected animals and was associated with enhanced frequencies of activated M. tuberculosis--specific IFN-γ--expressing CD4+ T cells. In WT mice, TNFRp75 shedding correlated with markedly reduced bioactive TNF levels and IL-12p40 expression. Neutralization of TNFRp75 in M. tuberculosis--infected WT BM-derived DCs (BMDCs) increased production of bioactive TNF and IL-12p40 to a level equivalent to that produced by TNFRp75-/- BMDCs. Addition of exogenous TNFRp75 to TNFRp75-/- BMDCs infected with M. tuberculosis decreased IL-12p40 synthesis, demonstrating that TNFRp75 shedding regulates DC activation. These data indicate that TNFRp75 shedding downmodulates protective immune function and reduces host resistance and survival; therefore, targeting TNFRp75 may be beneficial for improving disease outcome. [ABSTRACT FROM AUTHOR]

Leukocyte adhesion molecules are involved in cell recruitment in an allergic airway response and therefore provide a target for pharmaceutical intervention. Neutrophil inhibitory factor (NIF), derived from canine hookworm (Ancylostoma caninum), binds selectively and competes with the A-domain of CD11b for binding to ICAM-1. The effect of recombinant NIF was investigated. Intranasal administration of rNIF reduced pulmonary eosinophilic infiltration, goblet cell hyperplasia, and Th2 cytokine production inOVA-sensitized mice. In vitro, transendothelialmigration of human blood eosinophils across IL-4-activated umbilical vein endothelial cell (HUVEC) monolayers was inhibited by rNIF (IC50: 4.6 ± 2.6 nM; mean ± SEM), but not across TNF or IL-1-activated HUVEC monolayers. Treatment of eosinophils with rNIF together with mAb 60.1 directed against CD11b or mAb 107 directed against the metal ion-dependent adhesion site (MIDAS) of the CD11b A-domain resulted in no further inhibition of transendothelial migration suggesting shared functional epitopes. In contrast, rNIF increased the inhibitory effect of blocking mAbs against CD18, CD11a, and VLA-4. Together, we show that rNIF, a selective antagonist of the A-domain of CD11b, has a prominent inhibitory effect on eosinophil transendothelial migration in vitro, which is congruent to the in vivo inhibition of OVA-induced allergic lung inflammation. [ABSTRACT FROM AUTHOR]

Of those individuals who are infected with M. tuberculosis, 90% do not develop active disease and represents a large reservoir of M. tuberculosis with the potential for reactivation of infection. Sustained TNF expression is required for containment of persistent infection and TNF neutralization leads to tuberculosis reactivation. In this study, we investigated the contribution of soluble TNF (solTNF) and transmembrane TNF (Tm-TNF) in immune responses generated against reactivating tuberculosis. In a chemotherapy induced tuberculosis reactivation model, mice were challenged by aerosol inhalation infection with low dose M. tuberculosis for three weeks to establish infection followed chemotherapeutic treatment for six weeks, after which therapy was terminated and tuberculosis reactivation investigated. We demonstrate that complete absence of TNF results in host susceptibility to M. tuberculosis reactivation in the presence of established mycobacteria-specific adaptive immunity with mice displaying unrestricted bacilli growth and diffused granuloma structures compared to WT control mice. Interestingly, bacterial re-emergence is contained in Tm-TNF mice during the initial phases of tuberculosis reactivation, indicating that Tm-TNF sustains immune pressure as in WT mice. However, Tm-TNF mice show susceptibility to long term M. tuberculosis reactivation associated with uncontrolled influx of leukocytes in the lungs and reduced IL-12p70, IFNc and IL-10, enlarged granuloma structures, and failure to contain mycobacterial replication relative to WT mice. In conclusion, we demonstrate that both solTNF and Tm-TNF are required for maintaining immune pressure to contain reactivating M. tuberculosis bacilli even after mycobacteria-specific immunity has been established. [ABSTRACT FROM AUTHOR]

Abstract: There is interest in identifying the pattern recognition receptors involved in initiating protective or non-protective host responses to Mycobacterium tuberculosis (Mtb). Here we explored the role of the Syk/CARD9-coupled receptor, Dectin-1, using an aerosol model of Mtb infection in wild-type and Dectin-1 deficient mice. We observed a reduction in pulmonary bacilli burdens in the Dectin-1 deficient animals, but this did not correlate with significant changes in pulmonary pathology, cytokine levels or ability of these animals to survive the infection. Thus Dectin-1 makes a minor contribution to susceptibility to Mtb infections in mice. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor-α (TNF-α) plays a critical role in the recruitment and activation of mononuclear cells in mycobacterial infection. The role of membrane TNF, in host resistance against Mycobacterium bovis bacille Calmette–Guérin (BCG), was tested in knock-in mice in which the endogenous TNF was replaced by a non-cleavable and regulated allele (Δ1–12, TNFtm/tm). While 100% of mice with complete TNF deficiency (TNF−/−) succumbed to infection, 50% of TNFtm/tm mice were able to control M. bovis BCG infection and survived the experimental period. Membrane expressed TNF allowed a substantial recruitment of activated T cells and macrophages with granuloma formation and expression of bactericidal inducible nitric oxide synthase (iNOS). Using virulent Mycobacterium tuberculosis infection we confirm that membrane TNF conferred partial protection. Infection in TNFtm/tm double transgenic mice with TNF-R1 or TNF-R2 suggest protection is mediated through TNF-R2 signalling. Therefore, the data suggest that membrane-expressed TNF plays a critical role in host defence to mycobacterial infection and may partially substitute for soluble TNF. [ABSTRACT FROM AUTHOR]

Control of Trypanosoma congolense infections requires an early cell-mediated immune response. To unravel the role of tumor necrosis factor (TNF) in this process, 6 different T. congolense strains were used in 6 different gene-deficient mouse models that included TNF-/-, TNF receptor—1 (TNFp55)-/-, and TNF receptor—2 (TNFp75)-/- mice, 2 cell type—specific TNF-/- mice, as well as TNF—knock-in mice that expressed only membrane-bound TNF. Our results indicate that soluble TNF produced by macrophages/neutrophils and TNFp55 signaling are essential and sufficient to control arasitemia. The downstream mechanism in the control of T. congolense infection depends on inducible nitric oxide synthase activation in the liver. Such a role for nitric oxide is corroborated ex vivo, because the inhibitor NG-monomethyl-L-arginine blocks the trypanolytic activity of the adherent liver cell population, whereas exogenous interferon-γ that stimulates nitric oxide production enhances parasite killing. In conclusion, the control of T. congolense infection depends on macrophage/neutrophil-derived soluble TNF and intact TNFp55 signaling, which induces trypanolytic nitric oxide. [ABSTRACT FROM AUTHOR]

Background: Tumour necrosis factor (TNF) is crucial for the control of mycobacterial infection as TNF deficient (KO) die rapidly of uncontrolled infection with necrotic pneumonia. Here we investigated the role of membrane TNF for host resistance in knock-in mice with a non-cleavable and regulated allele (mem-TNF). Methods: C57BL/6, TNF KO and mem-TNF mice were infected with M. tuberculosis H37Rv (Mtb at 100 CFU by intranasal administration) and the survival, bacterial load, lung pathology and immunological parameters were investigated. Bone marrow and lymphocytes transfers were used to test the role of membrane TNF to confer resistance to TNF KO mice. Results: While TNF-KO mice succumbed to infection within 4-5 weeks, mem-TNF mice recruited normally T cells and macrophages, developed mature granuloma in the lung and controlled acute Mtb infection. However, during the chronic phase of infection mem-TNF mice succumbed to disseminated infection with necrotic pneumonia at about 150 days. Reconstitution of irradiated TNF-KO mice with mem-TNF derived bone marrow cells, but not with lymphocytes, conferred host resistance to Mtb infection in TNF-KO mice. Conclusion: Membrane expressed TNF is sufficient to allow cell-cell signalling and control of acute Mtb infection. Bone marrow cells, but not lymphocytes from mem-TNF mice confer resistance to infection in TNF-KO mice. Long-term infection control with chronic inflammation likely disrupting TNF mediated cell-cell signalling, additionally requires soluble TNF. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) such as TLR2 and TLR4 have been implicated in host response to mycobacterial infection. Here, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with Mycobacterium tuberculosis (MTB). While primary MyD88-/- macrophages and DCs are defective in TNF, IL- 12, and NO production in response to mycobacterial stimulation, the upregulation of costimulatory molecules CD40 and CD86 is unaffected. Aerogenic infection of MyD88-/- mice with MTB is lethal within 4 weeks with 2 log10 higher CFU in the lung; high pulmonary levels of cytokines and chemokines; and acute, necrotic pneumonia, despite a normal T cell response with IFN-γ production to mycobacterial antigens upon ex vivo restimulation. Vaccination with Mycobacterium bovis bacillus Calmette-Guérin conferred a substantial protection in MyD88-/- mice from acute MTB infection. These data demonstrate that MyD88 signaling is dispensable to raise an acquired immune response to MTB. Nonetheless, this acquired immune response is not sufficient to compensate for the profound innate immune defect and the inability of MyD88-/- mice to control MTB infection. [ABSTRACT FROM AUTHOR]

The phenothiazine-derived antipsychotic drugs, such as chlorpromazine and thioridazine, are bactericidal against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis , but produce undesirable side effects at clinically relevant doses. We have previously modified four novel phenothiazines and maintained their antimycobacterial activity. This study evaluated the pharmacological and toxicity profiles of these novel non-neuroleptic phenothiazines, PTZ3, PTZ4, PTZ31 and PTZ32, for their metabolic stability, kinetic solubility and potential cytotoxic effects in vitro. To further support the safet use of these drug candidates, the in vivo pharmacological and toxicity profiles were assessed in C57BL/6 mice via single or repeated oral gavage. In acute toxicity studies, all four modified phenothiazines showed favourable safety in mice. When treated daily with 100 mg/kg of PTZ3 and PTZ4 for 2 weeks, mice displayed no signs of toxicity. Alternatively, treatment with PTZ31 resulted in 20% mortality with no toxicity evident in biochemical or histological analysis, while exposure to PTZ32 resulted in a 45% survival with increased serum concentrations of uric acid and alkaline phosphatase. The combined non-neuroleptic and antimycobacterial effects of the novel phenothiazines PTZ3, PTZ4, PTZ31 and PTZ32 demonstrated favourable pharmacological and toxicity profiles in this study, highlight the potential of these compounds as suitable anti-tuberculosis drug candidates. Image 1 • The four non-neuroleptic phenothiazine drugs were non-toxic to the macrophages. • In vitro solubility and metabolic stability were evaluated. • All mice treated with modified phenothiazines survived in acute toxicity studies. • Repeated exposure of modified phenothiazines in mice were safer than thioridazine. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a deadly infectious disease. The thin pipeline of new drugs for TB, the ineffectiveness in adults of the only vaccine available, i.e. the Bacillus Calmette-Guerin vaccine, and increasing global antimicrobial resistance, has reinvigorated interest in immunotherapies. Nanoparticles (NPs) potentiate the effect of immune modulating compounds (IMC), enabling cell targeting, improved transfection of antigens, enhanced compound stability and provide opportunities for synergistic action, via delivery of multiple IMCs. In this review we describe work performed in the application of NPs towards achieving immune modulation for TB treatment and vaccination. Firstly, we present a comprehensive review of M. tuberculosis and how the bacterium modulates the host immune system. We find that current work suggest great promise of NP based immunotherapeutics as novel treatments and vaccination systems. There is need to intensify research efforts in this field, and rationally design novel NP immunotherapeutics based on current knowledge of the mycobacteriology and immune escape mechanisms employed by M. tuberculosis. [ABSTRACT FROM AUTHOR]

The pleiotropic activities of TNF are mediated by two structurally related but functionally distinct type I transmembrane receptors, p55TNFR and p75TNFR expressed in most cell types, that can be cleaved and act as TNF scavengers. Here, we investigated the effect of persistent p55TNFR cell surface expression during aerosol inhalation challenge with virulent M. tuberculosis H37Rv. We demonstrated that persistency of p55TNFR in macrophage cultures increased the synthesis of soluble TNF, p75TNFR and NO, however, had no effects on bacteria killing ability. Furthermore, it did not facilitate enhanced protection to primary acute M. tuberculosis infection in p55∆NS mice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55∆NS mice after M. tuberculosis challenge. Defective expressions of CD44 and INFγ attributed to an impaired T cell response during persistent p55TNFR expression that caused marginal transient susceptibility during chronic infection. Moreover, persistent p55TNFR expression induced early reactivation during latent tuberculosis infection. These data indicate a prominent role of p55TNFR shedding in Th1 mediated protection against chronic and latent tuberculosis infection. [ABSTRACT FROM AUTHOR]

Antibodies targeting IL-17A or its receptor IL-17RA show unprecedented efficacy in the treatment of autoimmune diseases such as psoriasis. These therapies, by neutralizing critical mediators of immunity, may increase susceptibility to infections. Here, we compared the effect of antibodies neutralizing IL-17A, IL-17F or TNFα on murine host responses to Mycobacterium tuberculosis infection by evaluating lung transcriptomic, microbiological and histological analyses. Coinciding with a significant increase of mycobacterial burden and pathological changes following TNFα blockade, gene array analyses of infected lungs revealed major changes of inflammatory and immune gene expression signatures 4 weeks post-infection. Specifically, gene expression associated with host-pathogen interactions, macrophage recruitment, activation and polarization, host-antimycobacterial activities, immunomodulatory responses, as well as extracellular matrix metallopeptidases, were markedly modulated by TNFα blockade. IL-17A or IL-17F neutralization elicited only mild changes of few genes without impaired host resistance four weeks after M. tuberculosis infection. Further, the absence of both IL-17RA and IL-22 pathways in genetically deficient mice did not profoundly compromise host control of M. tuberculosis over a 6-months period, ruling out potential compensation between these two pathways, while TNFα-deficient mice succumbed rapidly. These data provide experimental confirmation of the low clinical risk of mycobacterial infection under anti-IL-17A therapy, in contrast to anti-TNFα treatment. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear.Methods: We generated neuron-specific TNF-deficient (NsTNF(-/-)) mice and compared outcomes of disease against TNF(f/f) control and global TNF(-/-) mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA).Results: Intracerebral M. tuberculosis infection of TNF(-/-) mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF(-/-) mice were resistant to infection and presented with a phenotype similar to that in TNF(f/f) control mice. Impaired immunity in TNF(-/-) mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx.Conclusion: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB. [ABSTRACT FROM AUTHOR]