Faculty Opinions recommendation of Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling.

Leptospirosis, caused by pathogenic spirochetes, is a zoonotic disease of global importance. The detailed pathogenesis of leptospirosis is still unclear, which limits the ideal treatment of leptospirosis. In this study, we analyzed the expression of Toll-like receptor 2 (TLR2) and TLR4 in target organs of both resistant mice and susceptible hamsters after Leptospira interrogans serovar Autumnalis infection. TLR2 but not TLR4 transcripts in mouse organs contrasted with delayed induction and overexpression in hamster organs. Coinjection of leptospires and the TLR2 agonist Pam3CSK4 into hamsters improved their survival rate, alleviated tissue injury, and decreased the abundance of leptospires in target organs. The production of interleukin-10 (IL-10) from tissues was enhanced in hamsters of the group coinjected with leptospires and Pam3CSK4 compared with the leptospira-injected group. Similarly, IL-10 levels in TLR2-deficient mice were lower than those in wild-type mice. A high ratio of IL-10/tumor necrosis factor alpha (TNF-α) levels was found in both infected wild-type mice and hamsters coinjected with leptospires and Pam3CSK4. Moreover, TLR2-dependent IL-10 expression was detected in peritoneal macrophages after leptospira infection. Our data demonstrate that coinjection of leptospires and Pam3CSK4 alleviates the pathology of leptospirosis in hamsters; this effect may result from the enhanced expression of TLR2-dependent IL-10.

Download Full-text

Epithelial Cells Augment Barrier Function via Activation of the Toll-Like Receptor 2/Phosphatidylinositol 3-Kinase Pathway upon Recognition of Salmonella enterica Serovar Typhimurium Curli Fibrils in the Gut

Infection and Immunity ◽

10.1128/iai.00453-12 ◽

2012 ◽

Vol 81 (2) ◽

pp. 478-486 ◽

Cited By ~ 40

Author(s):

Gertrude O. Oppong ◽

Glenn J. Rapsinski ◽

Tiffanny N. Newman ◽

Jessalyn H. Nishimori ◽

Steven G. Biesecker ◽

...

Keyword(s):

Bacterial Translocation ◽

Intestinal Epithelium ◽

Salmonella Enterica ◽

Intestinal Epithelial ◽

Toll Like Receptor ◽

Wild Type ◽

Phosphatidylinositol 3 Kinase ◽

Serovar Typhimurium ◽

Toll Like Receptor 2 ◽

Phosphatidylinositol 3

ABSTRACTCurli fibrils, the best-characterized functional bacterial amyloids, are an important component of enterobacterial biofilms. We have previously shown that curli fibrils are recognized by the Toll-like receptor 2 (TLR2)/TLR1 heterodimer complex. Utilizing polarized T-84 cells, an intestinal epithelial cell line derived from colon carcinoma grown on semipermeable tissue culture inserts, we determined that infection with aSalmonella entericaserovar TyphimuriumcsgBAmutant, which does not express curli, resulted in an increase in intestinal barrier permeability and an increase in bacterial translocation compared to infection with curliated wild-typeS. Typhimurium. When the TLR2 downstream signaling molecule phosphatidylinositol 3-kinase (PI3K) was blocked using wortmannin or LY294002, the difference in disruption of the intestinal epithelium and bacterial translocation was no longer observed. Additionally, disruption of polarized T-84 cells treated basolaterally with the TLR5 ligand flagellin was prevented when the polarized cells were simultaneously treated with the synthetic TLR2/TLR1 ligand Pam3CSK4or with purified curli fibrils in the apical compartment. Similar toin vitroobservations, C57BL/6 mice infected with thecsgBAmutant suffered increased disruption of the intestinal epithelium and therefore greater dissemination of the bacteria to the mesenteric lymph nodes than mice infected with wild-typeS. Typhimurium. The differences in disruption of the intestinal epithelium and bacterial dissemination in the mice infected withcsgBAmutant or wild-typeS. Typhimurium were not apparent in TLR2-deficient mice. Overall, these studies report for the first time that activation of the TLR2/PI3K pathway by microbial amyloids plays a critical role in regulating the intestinal epithelial barrier as well as monitoring bacterial translocation during infection.

Download Full-text

Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00642.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. H503-H509 ◽

Cited By ~ 84

Author(s):

Yasushi Sakata ◽

Jian-Wen Dong ◽

Jesus G. Vallejo ◽

Chien-Hua Huang ◽

J. Scott Baker ◽

...

Keyword(s):

Myocardial Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Toll Like Receptor ◽

Wild Type ◽

Lv Dysfunction ◽

Toll Like Receptor 2 ◽

Myocardial Ischemia Reperfusion

Production of proinflammatory cytokines contributes to cardiac dysfunction during ischemia-reperfusion. The principal mechanism responsible for the induction of this innate stress response during periods of myocardial ischemia-reperfusion remains unknown. Toll-like receptor 2 (TLR2) is a highly conserved pattern recognition receptor that has been implicated in the innate immune response to a variety of pathogens. However, TLR2 may also mediate inflammation in response to noninfectious injury. We therefore hypothesized that TLR2 is essential for modulating myocardial inflammation and left ventricular (LV) function during ischemia-reperfusion injury. Susceptibility to myocardial ischemia-reperfusion injury following ischemia-reperfusion was determined in Langendorff-perfused hearts isolated from wild-type mice and mice deficient in TLR2 (TLR2D) and Toll interleukin receptor domain-containing adaptor protein. After ischemia-reperfusion, contractile performance was significantly impaired in hearts from wild-type mice as demonstrated by a lower recovery of LV developed pressure relative to TLR2D hearts. Creatinine kinase levels were similar in both groups after reperfusion. Contractile dysfunction in wild-type hearts was associated with elevated cardiac levels of TNF and IL-1β. Ischemia-reperfusion-induced LV dysfunction was reversed by treatment with the recombinant TNF blocking protein etanercept. These studies show for the first time that TLR2 signaling importantly contributes to the LV dysfunction that occurs following ischemia-reperfusion. Thus disruption of TLR2-mediated signaling may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury.

Download Full-text

Structure–activity correlations of variant forms of the B pentamer ofEscherichia colitype II heat-labile enterotoxin LT-IIb with Toll-like receptor 2 binding

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s0907444912038917 ◽

2012 ◽

Vol 68 (12) ◽

pp. 1604-1612 ◽

Cited By ~ 6

Author(s):

Vivian Cody ◽

Jim Pace ◽

Hesham F. Nawar ◽

Natalie King-Lyons ◽

Shuang Liang ◽

...

Keyword(s):

Structural Data ◽

Binding Activity ◽

Side Chain ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Wild Type ◽

B Subunit ◽

Heat Labile ◽

Pore Opening ◽

Toll Like Receptor 2

The pentameric B subunit of the type II heat-labile enterotoxin ofEscherichia coli(LT-IIb-B5) is a potent signaling molecule capable of modulating innate immune responses. It has previously been shown that LT-IIb-B5, but not the LT-IIb-B5Ser74Asp variant [LT-IIb-B5(S74D)], activates Toll-like receptor (TLR2) signaling in macrophages. Consistent with this, the LT-IIb-B5(S74D) variant failed to bind TLR2, in contrast to LT-IIb-B5and the LT-IIb-B5Thr13Ile [LT-IIb-B5(T13I)] and LT-IIb-B5Ser74Ala [LT-IIb-B5(S74A)] variants, which displayed the highest binding activity to TLR2. Crystal structures of the Ser74Asp, Ser74Ala and Thr13Ile variants of LT-IIb-B5have been determined to 1.90, 1.40 and 1.90 Å resolution, respectively. The structural data for the Ser74Asp variant reveal that the carboxylate side chain points into the pore, thereby reducing the pore size compared with that of the wild-type or the Ser74Ala variant B pentamer. On the basis of these crystallographic data, the reduced TLR2-binding affinity of the LT-IIb-B5(S74D) variant may be the result of the pore of the pentamer being closed. On the other hand, the explanation for the enhanced TLR2-binding activity of the LT-IIb-B5(S74A) variant is more complex as its activity is greater than that of the wild-type B pentamer, which also has an open pore as the Ser74 side chain points away from the pore opening. Data for the LT-IIb-B5(T13I) variant show that four of the five variant side chains point to the outside surface of the pentamer and one residue points inside. These data are consistent with the lack of binding of the LT-IIb-B5(T13I) variant to GD1a ganglioside.

Download Full-text

Identification of a Second Major Site for CD46 Binding in the Hemagglutinin Protein from a Laboratory Strain of Measles Virus (MV): Potential Consequences for Wild-Type MV Infection

Journal of Virology ◽

10.1128/jvi.77.11.6585.2003 ◽

2003 ◽

Vol 77 (11) ◽

pp. 6585-6585

Author(s):

Nicolas Massé ◽

Thomas Barrett ◽

Claude P. Muller ◽

T. Fabian Wild ◽

Robin Buckland

Keyword(s):

Measles Virus ◽

Laboratory Strain ◽

Wild Type ◽

Major Site ◽

Hemagglutinin Protein

Download Full-text

Toll-Like Receptor-2-Mediated C-C Chemokine Receptor 3 and Eotaxin-Driven Eosinophil Influx Induced by Mycobacterium bovis BCG Pleurisy

Infection and Immunity ◽

10.1128/iai.01326-06 ◽

2006 ◽

Vol 75 (3) ◽

pp. 1507-1511 ◽

Cited By ~ 22

Author(s):

Heloisa D'Ávila ◽

Patrícia E. Almeida ◽

Natália R. Roque ◽

Hugo C. Castro-Faria-Neto ◽

Patrícia T. Bozza

Keyword(s):

Mycobacterium Bovis ◽

Lipid Body ◽

Eosinophil Infiltration ◽

Toll Like Receptor ◽

Wild Type ◽

Body Formation ◽

Pleural Infection ◽

Toll Like Receptor 2 ◽

Deficient Mice ◽

Eosinophil Accumulation

ABSTRACT An acute and persistent eosinophil infiltration is observed during Mycobacterium bovis BCG pleural infection in mice. Eosinophil accumulation, lipid body formation, and eotaxin production were significantly reduced in BCG-infected Toll-like receptor-2 (TLR2)-deficient mice compared to wild-type mice. Neutralization of eotaxin or CCR3 drastically inhibited BCG-induced eosinophil accumulation and lipid body formation, indicating that BCG-induced eosinophil recruitment and activation is largely dependent of TLR2-mediated eotaxin generation.

Download Full-text

Toll-Like Receptor 2 Represses Nonpilus Adhesin-Induced Signaling in Acute Infections with the Pseudomonas aeruginosa pilA Mutant

Infection and Immunity ◽

10.1128/iai.72.8.4561-4569.2004 ◽

2004 ◽

Vol 72 (8) ◽

pp. 4561-4569 ◽

Cited By ~ 19

Author(s):

Eva Lorenz ◽

Diana C. Chemotti ◽

Karen Vandal ◽

Philippe A. Tessier

Keyword(s):

Pseudomonas Aeruginosa ◽

Host Response ◽

Lavage Fluid ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Acute Infections ◽

Associated Proteins ◽

Important Means ◽

Toll Like Receptor 2

ABSTRACT Expression of pili and associated proteins is an important means of host invasion by bacterial pathogens. Recent evidence has suggested that the binding of Pseudomonas aeruginosa through nonpilus adhesins may also be important in respiratory diseases, since adhesins bind mucins. Using wild-type C57BL/6 and TLR2KO mice, we compared the induction levels of the host response to P. aeruginosa that either expressed pili or lacked pilus expression due to a mutation in the structural gene pilA. In C57BL/6 mice, deletion of pili led to a decreased immune response, evidenced by a lower secretion of cytokines and a lack of neutrophil chemotaxis. By contrast, the P. aeruginosa pilA mutant induced a hyperresponsive phenotype in TLR2KO mice. TLR2KO mice showed an increased number of neutrophils in lavage fluid compared to the levels seen when either mouse strain was exposed to wild-type P. aeruginosa. Further analysis indicated that the increased neutrophil influx was associated with an increased expression of calgranulins, possibly through an induction of Toll-like receptor 4 (TLR4) expression. The hyperresponsive phenotype of TLR2KO mice exposed to the P. aeruginosa pilA mutant was associated with TLR4 induction and indicated that nonpilus adhesin-induced signaling was repressed by TLR2 function and, if not blocked by the host, could induce airway hyperresponsiveness.

Download Full-text

Identification of a Second Major Site for CD46 Binding in the Hemagglutinin Protein from a Laboratory Strain of Measles Virus (MV): Potential Consequences for Wild-Type MV Infection

Journal of Virology ◽

10.1128/jvi.76.24.13034-13038.2002 ◽

2002 ◽

Vol 76 (24) ◽

pp. 13034-13038 ◽

Cited By ~ 30

Author(s):

Nicolas Massé ◽

Thomas Barrett ◽

Claude P. Muller ◽

T. Fabian Wild ◽

Robin Buckland

Keyword(s):

Measles Virus ◽

Laboratory Strain ◽

Cell Receptor ◽

Respiratory Epithelium ◽

Wild Type ◽

Major Site ◽

Hemagglutinin Protein ◽

A Cell ◽

H Protein

ABSTRACT Natural or wild-type (wt) measles virus (MV) infection in vivo which is restricted to humans and certain monkeys represents an enigma in terms of receptor usage. Although wt MV is known to use the protein SLAM (CD150) as a cell receptor, many human tissues, including respiratory epithelium in which the infection initiates, are SLAM negative. These tissues are CD46 positive, but wt MV strains, unlike vaccinal and laboratory MV strains, are not thought to use CD46 as a receptor. We have identified a novel CD46 binding site at residues S548 and F549, in the hemagglutinin (H) protein from a laboratory MV strain, which is also present in wt H proteins. Our results suggest that although wt MV interacts with SLAM with high affinity, it also possesses the capacity to interact with CD46 with low affinity.

Download Full-text