Toll-Like Receptor 2-Deficient Mice Succumb to Mycobacterium tuberculosis Infection

Drennan, Michael; Nicolle, Delphine; Quesniaux, Valérie; Jacobs, Muazzam; Allie, Nasiema; Mpagi, Joseph; Frémond, Cécile; Wagner, Hermann; Kirschning, Carsten J.; Ryffel, Bernhard

doi:10.1016/s0002-9440(10)63095-7

Cited by 303 publications

(280 citation statements)

References 45 publications

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“…In our study, the induction of IL-1b by M. tuberculosis is mediated by pathways involving TLR2 and TLR6. These data are in line with the studies involving TLR2 for the recognition of mycobacteria [27,28], and the increased susceptibility to M. tuberculosis infection of TLR2 À/À mice [29]. TLR2 is a receptor for bacterial lipopeptides, which are recognized by TLR2/TLR1 or TLR2/TLR6 heterodimers [30,31].…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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

et al. 2009

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“…11,55 Similarly, whereas infection with either BCG or M.tb in the absence of TLR2 or TLR4 results in enhanced bacterial burden, it occurs to a higher magnitude after M.tb infection. 63,64 Thus, given the difference in virulence between M. bovis BCG and M.tb, the findings from our current study will need to be independently verified in a model of pulmonary M.tb infection when it becomes technically possible in the future.…”

Section: Discussionmentioning

confidence: 89%

Pulmonary Mycobacterial Granuloma

Shaler

Kugathasan

McCormick

et al. 2011

The American Journal of Pathology

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The granuloma, a hallmark of host defense against pulmonary mycobacterial infection, has long been believed to be an active type 1 immune environment. However, the mechanisms regarding why granuloma fails to eliminate mycobacteria even in immune-competent hosts, have remained largely unclear. By using a model of pulmonary Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, we have addressed this issue by comparing the immune responses within the airway luminal and granuloma compartments. We found that despite having a similar immune cellular profile to that in the airway lumen, the granuloma displayed severely suppressed type 1 immune cytokine but enhanced chemokine responses. Both antigen-presenting cells (APCs) and T cells in granuloma produced fewer type 1 immune molecules including tumor necrosis factor-␣ (TNF-␣), interferon-␥ (IFN-␥), and nitric oxide. As a result, the granuloma APCs developed a reduced capacity to phagocytose mycobacteria and to induce T-cell proliferation. To examine the molecular mechanisms, we compared the levels of immune suppressive cytokine IL-10 in the airway lumen and granuloma and found that both granuloma APCs and T cells produced much more IL-10. Thus, IL-10 deficiency restored type 1 immune activation within the granuloma while having a minimal effect within the airway lumen. Hence, our study provides the first experimental evidence that, contrary to the conventional belief, the BCG-induced lung granuloma represents a symbiotic host-microbe microenvironment characterized by suppressed type 1 immune activation.

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“…The lungs were fixed in 4% buffered formaldehyde for standard microscopic analysis, 3 mm sections were stained with haematoxylin and eosin (H&E) [62]. Neutrophil and erythrocyte accumulation in alveoli, disruption of alveolar septae and activation of alveolar epithelial cells were quantified using a semi-quantitative score with increasing severity of changes (0-5) as described previously [6,63]. Groups of 5-8 mice were included in each experiment and ten randomly selected high-power fields (400 Â magnifications) per animal were analyzed.…”

Section: Microscopy and Mpo Activity In Lungmentioning

confidence: 99%

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

et al. 2009

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Bacterial products (such as endotoxins and flagellin) trigger innate immune responses through TLRs. Flagellin-induced signalling involves TLR5 and MyD88 and, according to some reports, TLR4. Whereas epithelial and dendritic cells are stimulated by flagellin in vitro, the cell contribution to the in vivo response is still unclear. Here, we studied the respective roles of radioresistant and radiosensitive cells in flagellin-induced airway inflammation in mice. We found that i.n. delivery of flagellin elicits a transient change in respiratory function and an acute, pro-inflammatory response in the lungs, characterized by TLR5-and MyD88-dependent chemokine secretion and neutrophil recruitment. In contrast, TLR4, CD14 and TRIF were not essential for flagellin-mediated responses, indicating that TLR4 does not cooperate with TLR5 in the lungs. Respiratory function, chemokine secretion and airway infiltration by neutrophils were dependent on radioresistant, TLR5-expressing cells. Furthermore, lung haematopoietic cells also responded to flagellin by activating TNF-a production. We suggest that the radioresistant lung epithelial cells are essential for initiating early, TLR5-dependent signalling in response to flagellin and thus triggering the lung's innate immune responses.Key words: Chemokine . Epithelium . Flagellin . Lung inflammation . TLR5 IntroductionUpon challenge with respiratory pathogens, the airways rapidly develop a pro-inflammatory response initiated by environmental agents including microbe-associated molecular patterns such as Gram-negative bacteria LPS or endotoxins. This proinflammatory reaction plays an important role in the innate defense against respiratory pathogens [1,2]. Physiological changes induced by endotoxin inhalation include pulmonary Ã These authors contributed equally to this work. Eur. J. Immunol. 2009. 39: 1587-1596 DOI 10.1002 Innate immunity 1587 function and bronchoconstriction, cytokine and chemokine production, PMN recruitment, increased permeability of the alveolar epithelium and the associated endothelium [3][4][5][6]. TLR4 [7], together with MD-2, LPS-binding protein and CD14 detect endotoxins and play a critical role in the initiation of the pulmonary response to systemic and mucosal endotoxin administration [5,[8][9][10]. The pulmonary inflammation to endotoxin involves TLR4 signalling in both the parenchyma cells like endothelial and epithelial cells and the haematopoietic cells, i.e. monocytes, dendritic cells and neutrophils [11]. In addition, TLR4 signalling contributes to the development and progression of chronic respiratory disease including asthma [12][13][14][15][16].Flagellin is the major constituent of flagella from Gramnegative and Gram-positive bacteria. TLR5 has been identified as the main pattern recognition receptor required for flagellinmediated immune signalling [17]. TLR5 signalling depends on MyD88 and results in activation of MAPK, nuclear translocation of NF-kB and production of various pro-inflammatory cytokines and chemokines [18]. Moreover, a previous ...

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Toll-Like Receptor 2-Deficient Mice Succumb to Mycobacterium tuberculosis Infection

Abstract: Recognition of

Cited by 303 publications

References 45 publications

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

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

Pulmonary Mycobacterial Granuloma

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

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