TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to <i>Mycobacterium tuberculosis </i>

Báfica, André; Scanga, Charles A.; Feng, Carl G.; Leifer, Cynthia A.; Cheever, Allen W.; Sher, Alan

doi:10.1084/jem.20051782

Cited by 545 publications

(530 citation statements)

References 62 publications

(91 reference statements)

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“…Our finding that TLR9 ligation is necessary for optimal LM-induced IFN-␥ production by NKDC is the first report implicating TLR9 in the innate immune response to LM. This is consistent with the known importance of colocalization of TLR9 and pathogen DNA in intracellular compartments during recognition of other intracellular pathogens (38). Recently, Streptococcus pneumoniae and Neisseria meningitidis have been shown to activate TLR9 in human PBMC leading to the induction of NF-B and IL-8 (39).…”

Section: Discussionsupporting

confidence: 85%

NK Dendritic Cells Are Innate Immune Responders to Listeria monocytogenes Infection

Plitas

Chaudhry

Kingham

et al. 2007

The Journal of Immunology

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NK dendritic cells (NKDC) are recently described immunologic cells that possess both lytic and Ag-presenting function and produce prolific quantities of IFN-γ. The role of NKDC in innate immunity to bacterial infection is unknown. Because IFN-γ is important in the immune response to Listeria monocytogenes (LM), we hypothesized that NKDC play a critical role during LM infection in mice. We found that LM increased the frequency and activation state of NKDC in vivo. Using in vivo intracellular cytokine analysis, we demonstrated that NKDC are a major source of early IFN-γ during infection with LM. Adoptive transfer of wild-type NKDC into IFN-γ-deficient recipients that were subsequently infected with LM decreased bacterial burden in the liver and spleen and prolonged survival. In contrast, NK cells were depleted early during LM infection, produced less IFN-γ, and conferred less protection upon adoptive transfer into IFN-γ-deficient mice. In vitro, LM induction of IFN-γ secretion by NKDC depended on TLR9, in addition to IL-18 and IL-12. Our study establishes NKDC as innate immune responders to bacterial infection by virtue of their ability to secrete IFN-γ.

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Section: Discussionsupporting

confidence: 85%

NK Dendritic Cells Are Innate Immune Responders to Listeria monocytogenes Infection

Plitas

Chaudhry

Kingham

et al. 2007

The Journal of Immunology

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“…TLR9 was not significantly engaged in the induction of IL-1b. TLR9 À/À mice have shown only minor defects in pathogen clearance, while enhancing the effects of TLR2 deficiency [34].…”

Section: Discussionmentioning

confidence: 99%

“…TLR9 was not significantly engaged in the induction of IL-1b. TLR9 À/À mice have shown only minor defects in pathogen clearance, while enhancing the effects of TLR2 deficiency [34].Interesting new information is the involvement of NOD2 as a receptor mediating IL-1b production by M. tuberculosis. Eur.…”

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confidence: 99%

Transcriptional and inflammasome‐mediated pathways for the induction of IL‐1β production by Mycobacterium tuberculosis

et al. 2009

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Proinflammatory cytokines of the IL-1 family play an important role for the anti-mycobacterial host defense mechanisms. In the present study we have deciphered the pathways leading from recognition of Mycobacterium tuberculosis to the production and release of IL-1b, the most important member of the IL-1 family. By stimulating cells defective in various pattern recognition receptors, we could demonstrate that IL-1b production is induced by M. tuberculosis through pathways involving TLR2/TLR6 and NOD2 receptors. In contrast, TLR4, TLR9 and TLR1 receptors are not involved in IL-1b induction. Recognition of M. tuberculosis by TLR and NOD2 leads to transcription of proIL-1b through mechanisms involving ERK, p38 and Rip2, but not JNK. Interestingly, although caspase-1 is necessary for the processing of proIL-1b, activation of caspase-1 is not dependent on the stimulation of cells by M. tuberculosis. Monocytes expressed constitutively active caspase-1. The secretion of IL-1b is dependent on the activation of P2X7-induced pathways by endogenously released ATP. In conclusion, we have dissected the molecular mechanisms responsible for IL-1b production by M. tuberculosis, and that may contribute to a deeper knowledge of the mechanisms of cell activation by M. tuberculosis.Key words: Cytokines . Infections -bacterial . Inflammation IntroductionIt is estimated that approximately one-third of the world population is infected with Mycobacterium tuberculosis, the agent causing tuberculosis (TB), although only 5% of these individuals will eventually develop clinical disease. The WHO estimated that 1.6 million deaths resulted from TB in 2005, equaling 4400 deaths a day [1]. The highest rates of infection and especially the mortality are seen in the developing countries, and rates continue to climb in countries where the prevalence of HIV infection is high, despite the implementation of TB control programs [2]. Furthermore, the increased prevalence of multidrug-resistant strains of M. tuberculosis represents a challenge for treatment programmes [3]. 10.1002/eji.200839115 Eur. J. Immunol. 2009Immunol. . 39: 1914Immunol. -1922 Johanneke Kleinnijenhuis et al. 1914The first line of defense against M. tuberculosis is formed by alveolar macrophages, which ingest and sequester the bacilli within granulomatous structures. The control and resolution of the infection involve the activation of macrophages, in which activated T lymphocytes play a crucial role [4]. The release of proinflammatory cytokines such as IL-1b, TNF, IL-12 or IL-18 from monocytes and monocyte-derived macrophages induces the production of T-cell-derived cytokines, most importantly IFN-g, which in turn will activate macrophages for the killing and elimination of the microorganisms [5,6]. Patients with defects in receptors for IL-12 and IFN have an increased susceptibility to mycobacterial infections [7][8][9], while the association between low CD4 counts and TB is well-known in HIV-infected patients [2].While most of the research has focused on the mechanisms resp...

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“…While some groups found that TLR-mediated signalling is dispensable for protective immunity against M. tuberculosis [3][4][5][6], others suggested an essential contribution of TLR to protection [7][8][9]. The TLR contain a Toll/IL-1 receptor domain, which associates with the adaptor molecule MyD88.…”

Section: Introductionmentioning

confidence: 99%

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

et al. 2010

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Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting MU. IFN-c secreted by natural killer, CD4 Th 1 and CD8 T cells upon instruction by IL-12 and -18 activates MU to restrict mycobacterial growth. Production of both cytokines is induced by TLR signalling in DC and MU. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLR and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18 receptor promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 double KO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, the protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophildriven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against tuberculosis.Key words: IFN-c . IL-18 . Mouse . Neutrophils . Tuberculosis IntroductionDespite more than 125 years of research and development, tuberculosis (TB) remains the most hazardous bacterial infection worldwide with approximately 2 million people dying of the disease annually [1]. The risk of disease is increased by immunocompromising conditions such as AIDS emphasizing that T-cell immunity protects latently infected individuals against active TB. The innate immune response to Mycobacterium tuberculosis instructs acquired immunity in the initial stage, and executes effector mechanisms in the chronic stage.M. tuberculosis is usually transmitted via aerosols and establishes stable infection in the lung. There, M. tuberculosis is engulfed by MF and DC, which serve as host cells for mycobacterial survival and propagation. Binding of mycobacterial ligands to TLR-2, -4 and -9 promotes release of chemokines and proinflammatory cytokines, expression of adhesion molecules and attraction of MF, DC and PMN. Two crucial MF-and DCderived cytokines, , induce NK-cell activity and bias immunity towards a Th1 cell response characterized by profound 396IFN-g production, which is considered critical for protection against M. tuberculosis [2]. Activated MF express anti-mycobacterial molecules such as nitric oxide synthase (NOS)-2 (also known as inducible NOS) and LRG47 as well as cytokines such as TNF-a, which promotes granuloma formation within the infected tissue to sequester the bacilli from dissemination [2].Despite the prevailing assumption that resistance to M. tuberculosis infection depends on microbe sensing through TLR, their importance for mounting a protective immune response against M. tuberculosis remains controversial. While some groups found that TLR-mediated...

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TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis

Cited by 545 publications

References 62 publications

NK Dendritic Cells Are Innate Immune Responders to Listeria monocytogenes Infection

NK Dendritic Cells Are Innate Immune Responders to Listeria monocytogenes Infection

Transcriptional and inflammasome‐mediated pathways for the induction of IL‐1β production by Mycobacterium tuberculosis

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

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