TNF in host resistance to tuberculosis infection.
ABSTRACT 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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ABSTRACT: Mycobacterium tuberculosis continues to be one of the most successful pathogens on earth. Upon inhalation of M. tuberculosis by a healthy individual, the host immune system will attempt to eliminate these pathogens using a combination of immune defense strategies. These include the recruitment of macrophages and other phagocytes to the site of infection, production of cytokines that enhance the microbicidal capacity of the macrophages, as well as the activation of distinct subsets of leukocytes that work in concert to fight the infection. However, being as successful as it is, M. tuberculosis has evolved numerous strategies to subvert host immunity at virtual every level. As a consequence, one third of the world inhabitants carry M. tuberculosis, and tuberculosis continuous to cause disease in more than 8 million people with deadly consequences in well over 1 million patients each year. In this review, we discuss several of the strategies that M. tuberculosis employs to circumvent host immunity, as well as describe some of the mechanisms that the host uses to counter such subversive strategies. As for many other infectious diseases, the ultimate outcome is usually defined by the relative strength of the virulence strategies employed by the tubercle bacillus versus the arsenal of immune defense mechanisms of the infected host.Frontiers in Immunology 01/2014; 5:455.
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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.Seminars in Immunology 01/2014; · 5.93 Impact Factor
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ABSTRACT: Tuberculosis (TB) is caused by an infection of Mycobacterium tuberculosis (Mtb) and remains an enormous and increasing health burden worldwide. To date, Mycobacterium bovis Bacillus Calmette Guerin (BCG) is the only licensed anti-TB vaccine worldwide, which provides an important but limited protection from the Mtb infection. The development of alternative anti-TB vaccines is therefore urgently needed. Here we report, the generation of Ad5-CEAB, a recombinant adenovirus expressing Mtb antigens of CFP10, ESAT6, Ag85A and Ag85B proteins in a form of mixture. In order to evaluate the immunogenicity of Ad5-CEAB, mice were immunized with Ad5-CEAB by intranasal instillation three times with 2-week intervals. The results demonstrated that Ad5-CEAB elicited a strong antigen-specific immune response, particularly of the Th1 immune responses that were characterized by an increased ratio of IgG2a/IgG1 and secretions of Th1 type cytokines, IFN-γ, TNF-α, IL-2 and IL-12. In addition, the Ad5-CEAB also showed an ability to enhance humoral responses with a dramatically augmented antigen-specific serum IgG. Furthermore, an elevated sIgA were also found in the bronchoalveolar lavage fluid of the immunized mice, suggesting the elicitation of mucosal immune responses. These data indicate that Ad5-CEAB can induce a broad range of antigen-specific immune responses in vivo, which provides a promising and novel route for developing anti-TB vaccines and warrants further investigation.Molecular immunology. 06/2014; 62(1):86-95.