Relative contribution of IL‐1α, IL‐1β and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG

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.

Isoniazid‐induced control of Mycobacterium tuberculosis by primary human cells requires interleukin‐1 receptor and tumor necrosis factor

“…Cellular structures known as necrotic granulomas may promote bacterial dissemination and enhance Mtb transmission [2,3]. On the other hand, counter balance is supported by host recognition of Mtb, which induces cytokines such as IL-1β and TNF [4,5], two potent inflammatory mediators that suppress Mtb growth [4,6]. It has C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur.…”

“…Cellular structures known as necrotic granulomas may promote bacterial dissemination and enhance Mtb transmission [2,3]. On the other hand, counter balance is supported by host recognition of Mtb, which induces cytokines such as IL-1β and TNF [4,5], two potent inflammatory mediators that suppress Mtb growth [4,6]. It has been shown that these cytokines regulate intracellular bacterial growth in human macrophages, whether by recruitment of antimicrobial effector molecules [7] or induction of apoptotic cell death [8].…”

Lack of IL-1 Receptor–Associated Kinase-4 Leads to Defective Th1 Cell Responses and Renders Mice Susceptible to Mycobacterial Infection

“…Furthermore, IRAK-4 is an adaptor molecule downstream of IL-1R signaling. Bourigault et al (41) showed that IL-1 signaling is important for controlling M. tuberculosis infection but is dispensable for the host immune response to M. bovis BCG, although IL-1b is produced in response to both pathogens. However, treatment of IRAK 2/2 macrophages with IFN-g and IL-1b did not improve M. tuberculosis intracellular killing at 72 h postinfection.…”

“…2). Measurement of alveolar wall thickening in lungs is an important parameter to determine lung inflammation (41).…”

Role of IL-10 and TNF-α during Mycobacterium tuberculosis infection in murine alveolar macrophages

“…Rapid Mtb growth and the death of the host have been clearly demonstrated following TNF-a blockade in vitro, in vivo, and in knockout mouse models, revealing the protective role of this cytokine in Mtb infection (Bruns et al, 2009;Jozefowski et al, 2011;Bourigault et al, 2013;Roh et al, 2013). Conversely, IL-10 has been found at increased levels in tuberculosis patients, and elevated innate production of IL-10 is associated with greater susceptibility to this disease (Cooper et al, 2011;Sakamoto, 2012).…”