TNF in Host Resistance to Tuberculosis Infection

Molecular Immunology and Embryology UMR6218, Orleans University and CNRS, Orleans, France.
Current directions in autoimmunity 01/2010; 11:157-79. DOI: 10.1159/000289204
Source: PubMed


TNF is essential to control Mycobacterium tuberculosis infection and cannot be replaced by other proinflammatory cytokines. Overproduction of TNF may cause immunopathology, while defective TNF production results in uncontrolled infection. The critical role of TNF in the control of tuberculosis has been illustrated recently by primary and reactivation of latent infection in some patients under pharmacological anti-TNF therapy for rheumatoid arthritis or Crohn's disease. In this review, we discuss results of recent studies aimed at better understanding of molecular, cellular and kinetic aspects of TNF-mediated regulation of host-mycobacteria interactions. In particular, recent data using either mutant mice expressing solely membrane TNF or specific inhibitor sparing membrane TNF demonstrated that membrane TNF is sufficient to control acute M. tuberculosis infection. This is opening the way to selective TNF neutralization that might retain the desired anti-inflammatory effect but reduce the infectious risk.

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    • "On other hand secretion of CCL2 by Mtb infection may shares the similar effects like cellular recruitment, CXCR4 induction, and suppression of Mtb-specific Th1 immune response very much similar to those imposed by HIV-1. In addition to CCL2, Mtb and its cell wall constituents like lipo-arabinomannan (LAM), phosphatidylinositol (PIM), lipomannan (LM), and 19-kD Mtb protein (56), the 38-kD glycoprotein and HSP70 recognition by TLR4 (66) proline–proline-glutamic acid (PPE) protein Rv1168c (67, 68) by pattern recognition receptor (PPR) and C-type lectin receptor (69) result in secretion of pro-inflammatory cytokines and chemokines including TNF-α (5), CCL2 (54, 70, 71), IL-1α/β (5, 72), IFN-γ (56, 73), and IL-6 (74–76) that can trigger HIV-1 replication by activating HIV-LTR of the infected macrophages or CD4+ T cells eventually a high viremia. While the secreted inflammatory molecules can act in autocrine manner to activate HIV-LTR. "
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    ABSTRACT: Active tuberculosis remains the leading cause of death among the HIV-1 seropositive individuals. Although significant success has been achieved in bringing down the number of HIV/AIDS-related mortality and morbidity following implementation of highly active anti-retroviral therapy (HAART). Yet, co-infection of Mycobacterium tuberculosis (Mtb) has posed severe clinical and preventive challenges in our efforts to eradicate the virus from the body. Both HIV-1 and Mtb commonly infect macrophages and trigger production of host inflammatory mediators that subsequently regulate the immune response and disease pathogenesis. These inflammatory mediators can impose beneficial or detrimental effects on each pathogen and eventually on host. Among these, inflammatory C-C chemokines play a central role in HIV-1 and Mtb pathogenesis. However, their role in lung-specific mechanisms of HIV-1 and Mtb interaction are poorly understood. In this review we highlight current view on the role of C-C chemokines, more precisely CCL2, on HIV-1: Mtb interaction, potential mechanisms of action and adverse clinical consequences in a setting HIV-1/Mtb co-infection. Targeting common chemokine regulators of HIV-1/Mtb pathogenesis can be an attractive and potential anti-inflammatory intervention in HIV/AIDS-related comorbidities.
    Full-text · Article · Oct 2013 · Frontiers in Immunology
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    • "Regulation of TNF gene transcription is inducer- and cell type-specific and invovles the formation of higher-order enhancer complexes, or enhanceosomes, at the TNF promoter [27], [29], [30], [31], [32], [33], as well as distal regulatory sequences [27], [34], [35]. TNF plays a critical protective role in the innate and adaptive response to tuberculosis in humans and mice [36], [37]. For example, active TB was observed to develop at a high frequency in individuals latently infected with TB who were treated with a broadly neutralizing antibody against TNF for Crohn's disease or rheumatoid arthritis [38]. "
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    ABSTRACT: In T cells, the transcription factor nuclear factor of activated T cells p (NFATp) is a key regulator of the cytokine genes tumor necrosis factor (TNF) and interferon-γ (IFN-γ). Here, we show that NFATp-deficient (NFATp(-/-)) mice have a dramatic and highly significant increase in mortality after Mycobacterium tuberculosis (MTb) infection as compared to mortality of control animals after MTb infection. Animals deficient in NFATp have significantly impaired levels of TNF and IFN-γ transcription and protein expression in naïve or total CD4(+) T cells, but display wild-type levels of TNF mRNA or protein from MTb-stimulated dendritic cells (DC). The rapid mortality and disease severity observed in MTb-infected NFATp(-/-) mice is associated with dysregulated production of TNF and IFN-γ in the lungs, as well as with increased levels of TNF, in their serum. Furthermore, global blocking of TNF production by injection of a TNF neutralizaing agent at 6 weeks, but not 12 weeks, post-MTb-infection further decreased the survival rate of both wild-type and NFATp(-/-) mice, indicating an early role for TNF derived from cells from the monocyte lineage in containment of infection. These results thus demonstrate that NFATp plays a critical role in immune containment of TB disease in vivo, through the NFATp-dependent expression of TNF and IFN-γ in T cells.
    Full-text · Article · Jul 2012 · PLoS ONE
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    • "The roles of TNF-α and the T cell response in TB have been largely debated. Immunomodulatory agents that inhibit TNF-α have been associated with both positive and adverse outcomes in TB patients [17], [20], [21]. While this topic remains controversial, it is becoming increasingly evident that it is the balance of TNF-α and other cytokines that influences the outcome of TB [22]. "
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    ABSTRACT: Global control of tuberculosis (TB), an infectious disease that claims nearly 2 million lives annually, is hindered by the long duration of chemotherapy required for curative treatment. Lack of adherence to this intense treatment regimen leads to poor patient outcomes, development of new or additional drug resistance, and continued spread of M.tb. within communities. Hence, shortening the duration of TB therapy could increase drug adherence and cure in TB patients. Here, we report that addition of the United Stated Food and Drug Administration-approved phosphodiesterase inhibitors (PDE-Is) cilostazol and sildenafil to the standard TB treatment regimen reduces tissue pathology, leads to faster bacterial clearance and shortens the time to lung sterilization by one month, compared to standard treatment alone, in a murine model of TB. Our data suggest that these PDE-Is could be repurposed for use as adjunctive drugs to shorten TB treatment in humans.
    Full-text · Article · Feb 2012 · PLoS ONE
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