Abstract
TNF and IL-1 are major mediators involved in severe inflammatory diseases against which therapeutic neutralizing antibodies are developed. However, both TNF and IL-1 receptor pathways are essential for the control of Mycobacterium tuberculosis infection, and it is critical to assess the respective role of IL-1α, IL-1β, and TNF. Using gene-targeted mice we show that absence of both IL-1α and IL-1β recapitulates the uncontrolled M. tuberculosis infection with increased bacterial burden, exacerbated lung inflammation, high IFNγ, reduced IL-23 p19 and rapid death seen in IL-1R1-deficient mice. However, presence of either IL-1α or IL-1β in single-deficient mice is sufficient to control acute M. tuberculosis infection, with restrained bacterial burden and lung pathology, in conditions where TNF deficient mice succumbed within 4 weeks with overwhelming infection. Systemic infection by attenuated M. bovis BCG was controlled in the absence of functional IL-1 pathway, but not in the absence of TNF. Therefore, although both IL-1α and IL-1β are required for a full host response to virulent M. tuberculosis, the presence of either IL-1α or IL-1β allows some control of acute M. tuberculosis infection, and IL-1 pathway is dispensable for controlling M. bovis BCG acute infection. This is in sharp contrast with TNF, which is essential for host response to both attenuated and virulent mycobacteria and may have implications for anti-inflammatory therapy with IL-1β neutralizing antibodies.
Highlights
Tuberculosis (TB) is still a major health problem, with about one-third of the global population considered to be infected with Mycobacterium tuberculosis
Using gene-targeted mice we show that absence of both IL-1a and IL-1b recapitulates the uncontrolled M. tuberculosis infection with increased bacterial burden, exacerbated lung inflammation, high IFNg, reduced IL-23 p19 and rapid death seen in IL-1R1-deficient mice
In view of the increased lung weight indicative of a strong local inflammation in mice lacking IL-1a and/or IL-1b, and of the defective granuloma formation reported in IL-1R1 deficient mice [13], we addressed the relative contribution of IL-1a and IL-1b in granuloma formation upon M. tuberculosis infection
Summary
Tuberculosis (TB) is still a major health problem, with about one-third of the global population considered to be infected with Mycobacterium tuberculosis. Quantification of bacterial growth and death rates showed that M. tuberculosis replicates throughout the course of chronic tuberculosis infection in mice and is restrained by the host immune system [3]. Immunodepression of the host can favour a reactivation of latent tuberculosis infection. Neutralisation of TNF for the treatment of severe inflammatory diseases has been associated with reactivation of latent tuberculosis and increased susceptibility to primary tuberculosis infection [4,5,6,7], a risk that is still present when patients do not receive appropriate chemoprophylactic treatment [8]. Inhibiting IL-1 represents an interesting alternative to TNF neutralisation in severe inflammatory diseases [9], IL-1/IL-1R1 pathway seems
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
