Toll-Like Receptor 2 Is Required for Inflammatory Responses to<i>Francisella tularensis</i>LVS

Katz, Jannet; Zhang, Ping; Martin, Michael; Vogel, Stefanie N.; Michalek, Suzanne M.

doi:10.1128/iai.74.5.2809-2816.2006

Cited by 118 publications

(161 citation statements)

References 76 publications

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“…3A) and stated that: (1) there were, in fact, three intrarelated groups; (2) that the largest difference between any of the groups was between pre-vaccination and early post-vaccination; and (3) late post-vaccination was more similar to pre-vaccination than to early post-vaccination. Together, these data corroborate previous studies from our laboratory and others suggesting that the earliest responses to vaccination or infection may play key roles in anti-F. tularensis immune responses (Telepnev et al, 2005;Malik et al, 2006;Katz et al, 2006;Isherwood et al, 2005;Fuller et al, 2006;Elkins et al, 2003).…”

Section: Global Expression Pattern Analysis Yields Three Principal Grsupporting

confidence: 81%

Transcriptome analysis of human immune responses following live vaccine strain (LVS) Francisella tularensis vaccination

Fuller

Brittingham

Porter³

et al. 2007

Molecular Immunology

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The live vaccine strain (LVS) of Francisella tularensis is the only vaccine against tularemia available for humans, yet its mechanism of protection remains unclear. We probed human immunological responses to LVS vaccination with transcriptome analysis using PBMC samples from volunteers at time points pre-and post-vaccination. Gene modulation was highly uniform across all time points, implying commonality of vaccine responses. Principal components analysis revealed three highly distinct principal groupings: pre-vaccination (−144 h), early (+18 and +48 h), and late postvaccination (+192 and +336 h). The most significant changes in gene expression occurred at early post-vaccination time points (≤48 h), specifically in the induction of pro-inflammatory and innate immunity-related genes. Evidence supporting modulation of innate effector function, specifically antigen processing and presentation by dendritic cells, was especially apparent. Our data indicate that the LVS strain of F. tularensis invokes a strong early response upon vaccination. This pattern of gene regulation may provide insightful information regarding both vaccine efficacy and immunopathogenesis that may provide insight into infection with virulent strains of F. tularensis. Additionally, we obtained valuable information that should prove useful in evaluation of vaccine lots as well as efficacy testing of new anti-F. tularensis vaccines.

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Section: Global Expression Pattern Analysis Yields Three Principal Grsupporting

confidence: 81%

Transcriptome analysis of human immune responses following live vaccine strain (LVS) Francisella tularensis vaccination

Fuller

Brittingham

Porter³

et al. 2007

Molecular Immunology

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“…The weak proinflammatory activity of LPS from F. tularensis has been well described [17,18], and mice deficient in TLR4 are as susceptible to lethal tularemia as are naïve mice of the same background [16,52]. In contrast, recent reports have indicated an important role for TLR2 in the pathogenesis of tularemia [21,22,25,26]. The fact that recombinant LpnA induced inflammation in human macrophages in a manner that was dependent on TLR2 implicates it and other F. tularensis lipoproteins as important mediators of the host response in tularemia.…”

Section: Discussionmentioning

confidence: 82%

“…Together, these data suggest that F. tularensis possesses components other than LPS that are capable of initiating inflammation and regulating virulence. Recent findings have implicated TLR2, a receptor for lipoproteins, as important in the host response to infection with Francisella [21,22,25,26]. Therefore, the lipoproteins of F. tularensis may be important in the pathogenesis of tularemia.…”

Section: Introductionmentioning

confidence: 99%

“…The purified LPS of F. tularensis LVS does not stimulate production of tumor necrosis factor-α, interferon-γ, interleukin (IL)-12, IL-10, or nitric oxide by murine macrophages [17,18]. Nonetheless, F. tularensis LVS induces inflammation in mice in vivo [19,20] and can elicit the production of proinflammatory mediators by cultured murine macrophages and dendritic cells [21,22]. Further, human cells of innate immunity respond to culture with the LVS by producing an array of chemokines, cytokines, and adhesion molecules [23,24].…”

Section: Introductionmentioning

confidence: 99%

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A conserved and immunodominant lipoprotein of Francisella tularensis is proinflammatory but not essential for virulence

Forestal

Gil

Monfett

et al. 2008

Microbial Pathogenesis

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Francisella tularensis is a highly virulent bacterium that causes tularemia, a disease that is often fatal if untreated. A live vaccine strain (LVS) of this bacterium is attenuated for virulence in humans but produces lethal disease in mice. F. tularensis has been classified as a Category A agent of bioterrorism. Despite this categorization, little is known about the components of the organism that are responsible for causing disease in its hosts. Here, we report the deletion of a well-characterized lipoprotein of F. tularensis, designated LpnA (also known as Tul4), in the LVS. An LpnA deletion mutant was comparable to the wild-type strain in its ability to grow intracellularly and cause lethal disease in mice. Additionally, mice inoculated with a sublethal dose of the mutant strain were afforded the same protection against a subsequent lethal challenge with the LVS as were mice initially administered a sublethal dose of the wild-type bacterium. The LpnA-deficient strain showed an equivalent ability to promote secretion of chemokines by human monocyte-derived macrophages as its wild-type counterpart. However, recombinant LpnA potently stimulated primary cultures of human macrophages in a Toll-like receptor 2-dependent manner. Although human endothelial cells also were activated by recombinant LpnA, their response was relatively modest. LpnA is clearly unnecessary for multiple functions of the LVS, but its inflammatory capacity implicates it and other Francisella lipoproteins as potentially important to the pathogenesis of tularemia.

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“…C29 also significantly inhibited IL-8 mRNA in HEK-TLR2 cells stimulated by live F. tularensis (Fig. 1H), a TLR2/6 agonist (4,5,30). In primary murine macrophages derived from peritoneal exudate cells (PEC), C29 significantly blocked heat-killed S. pneumoniae (HKSP)-mediated and HKSA-mediated IL-1β mRNA (Fig.…”

Section: C29 Blocks Tlr2 Bacterial Agonist-induced Proinflammatory Genementioning

confidence: 99%

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

Mistry¹,

Laird²,

Schwarz³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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136

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Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C 16 H 15 NO 4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors.small molecule inhibitor | BB loop | TLR2 pocket | CADD T oll-like receptors (TLRs) are type I transmembrane receptors that detect conserved "pathogen-associated molecular patterns" from microbes, as well as host-derived "danger-associated molecular patterns" (1). TLR2 heterodimerizes with TLR6 or TLR1 to recognize diacyl lipopeptides or triacyl lipopeptides, respectively (2, 3), present in gram-positive and gram-negative bacteria (4-9).Ligand engagement of TLR2/1 or TLR2/6 activates the myeloid differentiation primary response gene 88 (MyD88)-dependent pathway (i.e., nuclear translocation of NF-κB, activation of MAPKs), resulting in production of proinflammatory cytokines (10). Dysregulated TLR2 signaling has been implicated in numerous diseases (e.g., sepsis, atherosclerosis, tumor metastasis, ischemia/reperfusion injury) (11)(12)(13)(14). Several inhibitors of TLR2 signaling have been developed (15-18), yet none is licensed for human use. A better understanding of the Toll/IL-1 receptor resistance (TIR) domain interactions involved in TLR2 signaling could lead to novel therapeutic agents.Both TLRs and adapter proteins contain a cytoplasmic TIR domain that mediates homotypic and heterotypic interactions ...

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Toll-Like Receptor 2 Is Required for Inflammatory Responses toFrancisella tularensisLVS

Cited by 118 publications

References 76 publications

Transcriptome analysis of human immune responses following live vaccine strain (LVS) Francisella tularensis vaccination

Transcriptome analysis of human immune responses following live vaccine strain (LVS) Francisella tularensis vaccination

A conserved and immunodominant lipoprotein of Francisella tularensis is proinflammatory but not essential for virulence

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

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