IL-1 Receptor-Mediated Signal Is an Essential Component of MyD88-Dependent Innate Response to Mycobacterium tuberculosis Infection

University of Orleans, Centre National de la Recherche Scientifique, Molecular Immunology and Embryology, Orleans, France.
The Journal of Immunology (Impact Factor: 4.92). 08/2007; 179(2):1178-89. DOI: 10.4049/jimmunol.179.2.1178
Source: PubMed


MyD88, the common adapter involved in TLR, IL-1, and IL-18 receptor signaling, is essential for the control of acute Mycobacterium tuberculosis (MTB) infection. Although TLR2, TLR4, and TLR9 have been implicated in the response to mycobacteria, gene disruption for these TLRs impairs only the long-term control of MTB infection. Here, we addressed the respective role of IL-1 and IL-18 receptor pathways in the MyD88-dependent control of acute MTB infection. Mice deficient for IL-1R1, IL-18R, or Toll-IL-1R domain-containing adaptor protein (TIRAP) were compared with MyD88-deficient mice in an acute model of aerogenic MTB infection. Although primary MyD88-deficient macrophages and dendritic cells were defective in cytokine production in response to mycobacterial stimulation, IL-1R1-deficient macrophages exhibited only a reduced IL-12p40 secretion with unaffected TNF, IL-6, and NO production and up-regulation of costimulatory molecules CD40 and CD86. Aerogenic MTB infection of IL-1R1-deficient mice was lethal within 4 wk with 2-log higher bacterial load in the lung and necrotic pneumonia but efficient pulmonary CD4 and CD8 T cell responses, as seen in MyD88-deficient mice. Mice deficient for IL-18R or TIRAP controlled acute MTB infection. These data demonstrate that absence of IL-1R signal leads to a dramatic defect of early control of MTB infection similar to that seen in the absence of MyD88, whereas IL-18R and TIRAP are dispensable, and that IL-1, together with IL-1-induced innate response, might account for most of MyD88-dependent host response to control acute MTB infection.

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Available from: Isabelle Maillet, Feb 13, 2014
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    • "To date several cytokines have been shown to participate in the innate host response against Mtb, where they can either function to confer host resistance or act as regulatory molecules that may exacerbate the infection (O'Garra et al., 2013). Studies have established the critical role of inflammatory cytokines, such as interleukin-1b (IL-1b), in the containment of Mtb by enhancing the antimicrobial function of macrophages (Fremond et al., 2007). On the contrary, animal models and studies in humans have revealed that type I interferons (IFNs) have probacterial activity and are associated with disease progression in TB (Berry et al., 2010; Manca et al., 2005; Stanley et al., 2007). "
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    ABSTRACT: Cytosolic detection of microbial products is essential for the initiation of an innate immune response against intracellular pathogens such as Mycobacterium tuberculosis (Mtb). During Mtb infection of macrophages, activation of cytosolic surveillance pathways is dependent on the mycobacterial ESX-1 secretion system and leads to type I interferon (IFN) and interleukin-1β (IL-1β) production. Whereas the inflammasome regulates IL-1β secretion, the receptor(s) responsible for the activation of type I IFNs has remained elusive. We demonstrate that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for initiating an IFN response to Mtb infection. cGAS associates with Mtb DNA in the cytosol to stimulate cyclic GAMP (cGAMP) synthesis. Notably, activation of cGAS-dependent cytosolic host responses can be uncoupled from inflammasome activation by modulating the secretion of ESX-1 substrates. Our findings identify cGAS as an innate sensor of Mtb and provide insight into how ESX-1 controls the activation of specific intracellular recognition pathways. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 06/2015; 17(6). DOI:10.1016/j.chom.2015.05.003 · 12.33 Impact Factor
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    • "This has given rise to the assumption that recognition of M. tuberculosis involves multiple redundant interactions with numerous PRRs. While the susceptibility of the MyD88-deficient mice to TB has been ascribed to defects in IL-1 receptor signaling (Fremond et al., 2007), the receptor(s) involved in the Card9-deficient phenotype has not been fully defined. Card9 is an essential component of the intracellular signaling pathway utilized by CLRs, and loss of this molecule leads to neutrophil-mediated pulmonary inflammation and rapid death in infected mice (Dorhoi et al., 2010). "
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    ABSTRACT: The interaction of microbes with pattern recognition receptors (PRRs) is essential for protective immunity. While many PRRs that recognize mycobacteria have been identified, none is essentially required for host defense in vivo. Here, we have identified the C-type lectin receptor CLECSF8 (CLEC4D, MCL) as a key molecule in anti-mycobacterial host defense. Clecsf8(-/-) mice exhibit higher bacterial burdens and increased mortality upon M. tuberculosis infection. Additionally, Clecsf8 deficiency is associated with exacerbated pulmonary inflammation, characterized by enhanced neutrophil recruitment. Clecsf8(-/-) mice show reduced mycobacterial uptake by pulmonary leukocytes, but infection with opsonized bacteria can restore this phagocytic defect as well as decrease bacterial burdens. Notably, a CLECSF8 polymorphism identified in humans is associated with an increased susceptibility to pulmonary tuberculosis. We conclude that CLECSF8 plays a non-redundant role in anti-mycobacterial immunity in mouse and in man. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Host & Microbe 02/2015; 17(2):252-259. DOI:10.1016/j.chom.2015.01.004 · 12.33 Impact Factor
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    • "Mice with a deficiency in IL-1R developed lethal infection characterized by extremely high numbers of Mtb in their lungs. Of note, a characteristic feature of lethal infection was an elevated (but not a deficient) production of major proinflammatory cytokines, e.g., IL-1, IL-6, TNF- (Fremond et al., 2007). "

    01/2015; 06(01). DOI:10.4172/2155-9899.1000298
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