scholarly journals Role for Toll-Like Receptor 2 in the Immune Response to Streptococcus pneumoniae Infection in Mouse Otitis Media

2009 ◽  
Vol 77 (7) ◽  
pp. 3100-3108 ◽  
Author(s):  
Fengchan Han ◽  
Heping Yu ◽  
Cong Tian ◽  
Shengli Li ◽  
Michael R. Jacobs ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Otitis Media ◽  
Middle Ear ◽  
Toll Like Receptor ◽  
Mrna Accumulation ◽  
Necrosis Factor Alpha ◽  
Acridine Orange Staining ◽  
Toll Like Receptor 2 ◽  
Factor Alpha

ABSTRACT Streptococcus pneumoniae is the most common pathogen associated with otitis media. To examine the role of Toll-like receptor 2 (TLR2) in host defense against Streptococcus pneumoniae infection in the middle ear, wild-type (WT; C57BL/6) and TLR2-deficient (TLR2−/−) mice were inoculated with Streptococcus pneumoniae (1 × 106 CFU) through the tympanic membrane. Nineteen of 37 TLR2−/− mice showed bacteremia and died within 3 days after the challenge, compared to only 4 of 32 WT mice that died. Of those that survived, more severe hearing loss in the TLR2−/− mice than in the WT mice was indicated by an elevation in auditory-evoked brain stem response thresholds at 3 or 7 days postinoculation. The histological pathology was characterized by effusion and tissue damage in the middle ear, and in the TLR2−/− mice, the outcome of infection became more severe at 7 days. At both 3 and 7 days postchallenge, the TLR2−/− mice had higher blood bacterial titers than the WT mice (P < 0.05), and typical bacteria were identified in the effusion from both ears of both mouse groups by acridine orange staining. Moreover, by 3 days postchallenge, the mRNA accumulation levels of NF-κB, tumor necrosis factor alpha, interleukin 1β, MIP1α, Muc5ac, and Muc5b were significantly lower in the ears of TLR2−/− mice than in WT mice. In summary, TLR2−/− mice may produce relatively low levels of proinflammatory cytokines following pneumococcal challenge, thus hindering the clearance of bacteria from the middle ear and leading to sepsis and a high mortality rate. This study provides evidence that TLR2 is important in the molecular pathogenesis and host response to otitis media.

scholarly journals Toll-Like Receptor 9 Is Required for Full Host Resistance toMycobacteriumaviumInfection but Plays No Role in Induction of Th1 Responses

2011 ◽  
Vol 79 (4) ◽  
pp. 1638-1646 ◽  
Author(s):  
Natália B. Carvalho ◽  
Fernanda S. Oliveira ◽  
Fernanda V. Durães ◽  
Leonardo A. de Almeida ◽  
Manuela Flórido ◽  
...  
Keyword(s):  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Histocompatibility Complex ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Myd88 Signaling ◽  
Necrosis Factor

ABSTRACTTo investigate the role of Toll-like receptor 9 (TLR9) in innate immunity toMycobacteriumavium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control ofM.aviuminfection. However, TLR9 KO or TLR2 KO spleen cells displayed normalM.avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4+T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production byM.avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes inM.avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control ofM.aviuminfection is not related to the induction of Th1 responses.

scholarly journals Macrophage-Elicited Osteoclastogenesis in Response to Bacterial Stimulation Requires Toll-Like Receptor 2-Dependent Tumor Necrosis Factor-Alpha Production

2007 ◽  
Vol 76 (2) ◽  
pp. 812-819 ◽  
Author(s):  
Takashi Ukai ◽  
Hiromichi Yumoto ◽  
Frank C. Gibson ◽  
Caroline Attardo Genco
Keyword(s):  
Tumor Necrosis Factor ◽  
Cell Surface ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The receptor activator of NF-κB ligand (RANKL) and the proinflammatory cytokines are believed to play important roles in osteoclastogenesis. We recently reported that the innate immune recognition receptor, Toll-like receptor 2 (TLR2), is crucial for inflammatory bone loss in response to infection by Porphyromonas gingivalis, the primary organism associated with chronic inflammatory periodontal disease. However, the contribution of macrophage-expressed TLRs to osteoclastogenesis has not been defined. In this study, we defined a requirement for TLR2 in tumor necrosis factor-alpha (TNF-α)-elicited osteoclastogenesis in response to exposure to P. gingivalis. Culture supernatant (CS) fluids from P. gingivalis-stimulated macrophages induced bone marrow macrophage-derived osteoclastogenesis. This activity was dependent on TNF-α and occurred independently of RANKL, interleukin-1β (IL-1β), and IL-6. CS fluids from P. gingivalis-stimulated TLR2−/− macrophages failed to express TNF-α, and these fluids induced significantly less osteoclast formation compared with that of the wild-type or the TLR4−/− macrophages. In addition, P. gingivalis exposure induced up-regulation of TLR2 expression on the cell surface of macrophages, which was demonstrated to functionally react to reexposure to P. gingivalis, as measured by a further increase in TNF-α production. These results demonstrate that macrophage-dependent TLR2 signaling is crucial for TNF-α-dependent/RANKL-independent osteoclastogenesis in response to P. gingivalis infection. Furthermore, the ability of P. gingivalis to induce the cell surface expression of TLR2 may contribute to the chronic inflammatory state induced by this pathogen.

scholarly journals Pulmonary and Systemic Host Response to Streptococcus pneumoniae and Klebsiella pneumoniae Bacteremia in Normal and Immunosuppressed Mice

2001 ◽  
Vol 69 (9) ◽  
pp. 5294-5304 ◽  
Author(s):  
Erjian Wang ◽  
Nathalie Ouellet ◽  
Marie Simard ◽  
Isabelle Fillion ◽  
Yves Bergeron ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Klebsiella Pneumoniae ◽  
Host Response ◽  
Necrosis Factor Alpha ◽  
Leukocyte Depletion ◽  
Pulmonary Capillary ◽  
Bacteremic Pneumonia ◽  
Factor Alpha ◽  
Immunocompetent Mice

ABSTRACT Mortality related to bacteremic pneumonia remains high, and the role of sepsis in inflammation, pulmonary injury, and death remains unclear, mostly in leukopenic states. In the present study, the microbiology, histopathology, and host response to Streptococcus pneumoniae and Klebsiella pneumoniae infection were determined in an experimental model of bacteremia in immunocompetent and leukopenic mice. Leukocyte depletion by cyclophosphamide did not impair the early clearance of pneumococci from blood but facilitated growth in lungs. By contrast, klebsiellae rapidly grew in blood of leukopenic mice. These observations suggest that tissue-based phagocytes and circulating leukocytes, respectively, play prominent roles in S. pneumoniae and K. pneumoniaeeradication. The kinetics of leukocyte recruitment in lungs duringS. pneumoniae bacteremia suggested early strong inflammation in immunocompetent mice that is associated with tumor necrosis factor alpha release and histological disorders, including cell debris and surfactant in alveolar spaces. Leukocyte depletion further stimulated pulmonary capillary leakage both in S. pneumoniae and K. pneumoniae bacteremia, which seemed attributable to bacterial virulence factors. Nitric oxide production did not differ significantly among groups. Leukopenia and low platelet counts characterized the late stage of bacteremia for both strains, but only K. pneumoniae altered renal function. Understanding the pathogenesis of bacteremia will help establish beneficial therapies for both sepsis and pneumonia.

scholarly journals The Absence of Toll-Like Receptor 4 Signaling in C3H/HeJ Mice Predisposes Them to Overwhelming Rickettsial Infection and Decreased Protective Th1 Responses

2008 ◽  
Vol 76 (8) ◽  
pp. 3717-3724 ◽  
Author(s):  
Jeffrey M. Jordan ◽  
Michael E. Woods ◽  
Juan Olano ◽  
David H. Walker
Keyword(s):  
Rickettsia Conorii ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tlr4 Signaling ◽  
Rickettsial Infections ◽  
Factor Alpha ◽  
Intravenous Inoculation

ABSTRACT The importance of toll-like receptor 4 (TLR4) in immunity to rickettsiae remains elusive. To investigate the role of TLR4 in protection against rickettsioses, we utilized C3H/HeJ mice, which are naturally defective in TLR4 signaling, and compared the responses of C3H/HeN and C3H/HeJ mice following intravenous inoculation with Rickettsia conorii. Mice genetically defective in TLR4 signaling developed overwhelming, fatal rickettsial infections when given an inoculum that was nonfatal for TLR4-competent mice. In addition, mice lacking the ability to signal through TLR4 had significantly greater rickettsial burdens in vivo. Moreover, we observed greater concentrations of the cytokines interleukin 6 (IL-6), tumor necrosis factor alpha, IL-12p40, IL-12p70, and IL-17 in the sera of mice with intact TLR4 function as well as significantly greater quantities of activated CD4+ and CD8+ T lymphocytes. Additionally, we also observed that Th17 cells were present only in TLR4-competent mice, suggesting an important role for TLR4 ligation in the activation of this subset. In agreement with these data, we also observed significantly greater percentages of immunosuppressive regulatory T cells in the spleen during infection in TLR4-defective mice. Together, these data demonstrate that, while rickettsiae do not contain endotoxic lipopolysaccharide, they nevertheless initiate TLR4-specific immune responses, and these responses are important in protection.

scholarly journals Role of Toll-Like Receptor 4 in the Proinflammatory Response to Vibrio cholerae O1 El Tor Strains Deficient in Production of Cholera Toxin and Accessory Toxins

2005 ◽  
Vol 73 (9) ◽  
pp. 6157-6164 ◽  
Author(s):  
G. Kenneth Haines ◽  
Blayne Amir Sayed ◽  
Melissa S. Rohrer ◽  
Verena Olivier ◽  
Karla J. Fullner Satchell
Keyword(s):  
Vibrio Cholerae ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Vibrio Cholerae O1 ◽  
Factor Alpha ◽  
El Tor ◽  
Necrosis Factor

ABSTRACT Following intranasal inoculation, Vibrio cholerae KFV101 (ΔctxAB ΔhapA ΔhlyA ΔrtxA) colonizes and stimulates tumor necrosis factor alpha and interleukin 1β (IL-1β) in mice, similar to what occurs with isogenic strain P4 (ΔctxAB), but is less virulent and stimulates reduced levels of IL-6, demonstrating a role for accessory toxins in pathogenesis. Morbidity is enhanced in C3H/HeJ mice, indicating that Toll-like receptor 4 is important for infection containment.

scholarly journals Glucocorticoids and Tumor Necrosis Factor Alpha Cooperatively Regulate Toll-Like Receptor 2 Gene Expression

2004 ◽  
Vol 24 (11) ◽  
pp. 4743-4756 ◽  
Author(s):  
Marcela A. Hermoso ◽  
Tetsuya Matsuguchi ◽  
Kathleen Smoak ◽  
John A. Cidlowski
Keyword(s):  
Innate Immunity ◽  
Transcription Factors ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Tumor necrosis factor alpha (TNF-α) and glucocorticoids are widely recognized as mutually antagonistic regulators of adaptive immunity and inflammation. Surprisingly, we show here that they cooperatively regulate components of innate immunity. The Toll-like receptor 2 (TLR2) gene encodes a transmembrane receptor critical for triggering innate immunity. Although TLR2 mRNA and protein are induced by inflammatory molecules such as TNF-α, we show that TLR2 is also induced by the anti-inflammatory glucocorticoids in cells where they also regulate MKP-1 mRNA and protein levels. TNF-α and glucocorticoids cooperate to regulate the TLR2 promoter, through the involvement of a 3′ NF-κB site, a STAT-binding element, and a 3′ glucocorticoid response element (GRE). Molecular studies show that the IκBα superrepressor or a STAT dominant negative element prevented TNF-α and dexamethasone stimulation of TLR2 promoter. Similarly, an AF-1 deletion mutant of glucocorticoid receptor or ablation of a putative GRE notably reduced the cooperative regulation of TLR2. Using chromatin immunoprecipitation assays, we demonstrate that all three transcription factors interact with both endogenous and transfected TLR2 promoters after stimulation by TNF-α and dexamethasone. Together, these studies define novel signaling mechanism for these three transcription factors, with a profound impact on discrimination of innate and adaptive immune responses.

scholarly journals Staphylococcus aureus Peptidoglycan Is a Toll-Like Receptor 2 Activator: a Reevaluation

2005 ◽  
Vol 73 (8) ◽  
pp. 5212-5216 ◽  
Author(s):  
Roman Dziarski ◽  
Dipika Gupta
Keyword(s):  
Staphylococcus Aureus ◽  
Sodium Dodecyl ◽  
Lipoteichoic Acid ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Phenol Extraction ◽  
Tlr2 Activation ◽  
Toll Like Receptor 2 ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Since the ability of peptidoglycan (PGN) to activate Toll-like receptor 2 (TLR2) was recently questioned, we reevaluated activation of TLR2 by PGN. Polymeric soluble or insoluble Staphylococcus aureus PGN, repurified by sodium dodecyl sulfate or phenol extraction, activated TLR2 at 0.1 to 1 or 10 μg/ml, respectively, and induced tumor necrosis factor alpha production. The TLR2 activation by PGN, but not by lipoteichoic acid, was abolished by muramidase digestion. We conclude that polymeric S. aureus PGN is a TLR2 activator.

scholarly journals The Staphylococcus aureus Lipoprotein SitC Colocalizes with Toll-Like Receptor 2 (TLR2) in Murine Keratinocytes and Elicits Intracellular TLR2 Accumulation

2010 ◽  
Vol 78 (10) ◽  
pp. 4243-4250 ◽  
Author(s):  
P. Müller ◽  
M. Müller-Anstett ◽  
J. Wagener ◽  
Q. Gao ◽  
S. Kaesler ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Cells ◽  
Hek293 Cells ◽  
Toll Like Receptor ◽  
Intracellular Accumulation ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Tlr2 Activation ◽  
Toll Like Receptor 2 ◽  
Factor Alpha

ABSTRACT SitC is one of the predominant lipoproteins in Staphylococcus aureus. Recently, SitC was shown to be capable of stimulating Toll-like receptor 2 (TLR2), but the mechanism of TLR2 activation by SitC has not been analyzed in detail so far. In this study, we purified C-terminally His-tagged SitC (SitC-His) from Staphylococcus aureus. SitC-His induced interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) release in human monocytes and also NF-κB activation in TLR2-transfected HEK293 cells, indicating TLR2-specific activation. SitC not only induced a TLR2-dependent release of IL-6 in primary murine keratinocytes (MKs) but also induced intracellular accumulation of TLR2, which was time and concentration dependent. Cy2-labeled SitC-His colocalized specifically with TLR2 in MKs and was also internalized in TLR2 knockout MKs, suggesting a TLR2-independent uptake. Neither activation nor colocalization of SitC-His was observed with TLR4 or Nod2. The results show that the native lipoprotein SitC-His specifically colocalizes with TLR2, is internalized by host cells, induces proinflammatory cytokines, and triggers intracellular accumulation of TLR2.

scholarly journals Role of Bacillus anthracis Spore Structures in Macrophage Cytokine Responses

2007 ◽  
Vol 75 (5) ◽  
pp. 2351-2358 ◽  
Author(s):  
Subhendu Basu ◽  
Tae Jin Kang ◽  
Wilbur H. Chen ◽  
Matthew J. Fenton ◽  
Les Baillie ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Cytokine Response ◽  
Innate Immune ◽  
Enzyme Linked Immunosorbent Assay ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Macrophage Cytokine ◽  
Necrosis Factor

ABSTRACT The innate immune response of macrophages (Mφ) to spores, the environmentally acquired form of Bacillus anthracis, is poorly characterized. We therefore examined the early Mφ cytokine response to B. anthracis spores, before germination. Mφ were exposed to bacilli and spores of Sterne strain 34F2 and its congenic nongerminating mutant (ΔgerH), and cytokine expression was measured by real-time PCR and an enzyme-linked immunosorbent assay. The exosporium spore layer was retained (exo+) or removed by sonication (exo−). Spores consistently induced a strong cytokine response, with the exo− spores eliciting a two- to threefold-higher response than exo+ spores. The threshold for interleukin-1β (IL-1β) production by wild-type Mφ was significantly lower than that required for tumor necrosis factor alpha expression. Cytokine production was largely dependent on MyD88, suggesting Toll-like receptor involvement; however, the expression of beta interferon in MyD88−/− Mφ suggests involvement of a MyD88-independent pathway. We conclude that (i) the B. anthracis spore is not immunologically inert, (ii) the exosporium masks epitopes recognized by the Mφ, (iii) the Mφ cytokine response to B. anthracis involves multiple pattern recognition receptors and signaling pathways, and (iv) compared to other cytokines, IL-1β is expressed at a lower spore concentration.

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