Dependence of Bacterial Protein Adhesins on Toll-Like Receptors for Proinflammatory Cytokine Induction

Hajishengallis, George; Martin, Michael; Sojar, Hakimuddin T.; Sharma, Ashu; Schifferle, Robert E.; DeNardin, Ernesto; Russell, Michael W.; Genco, Robert J.

doi:10.1128/cdli.9.2.403-411.2002

Cited by 82 publications

(116 citation statements)

References 57 publications

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“…Thus, they appear to be ideal ligands for a pattern recognition receptor. Interestingly, BspA interacts also with other pattern recognition receptors, such as the Toll-like receptor TLR2 (41), and recent findings suggest that Lrr domains are needed for this interaction (42). Thus, it may be that Lrr domains can serve as recognition motifs for other pattern recognition receptors as well.…”

Section: Discussionmentioning

confidence: 99%

Leucine-rich Repeats of Bacterial Surface Proteins Serve as Common Pattern Recognition Motifs of Human Scavenger Receptor gp340

Loimaranta¹,

Hytönen

Pulliainen

et al. 2009

Journal of Biological Chemistry

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Scavenger receptors are innate immune molecules recognizing and inducing the clearance of non-host as well as modified host molecules. To recognize a wide pattern of invading microbes, many scavenger receptors bind to common pathogenassociated molecular patterns, such as lipopolysaccharides and lipoteichoic acids. Similarly, the gp340/DMBT1 protein, a member of the human scavenger receptor cysteine-rich protein family, displays a wide ligand repertoire. The peptide motif VEVLXXXXW derived from its scavenger receptor cysteine-rich domains is involved in some of these interactions, but most of the recognition mechanisms are unknown. In this study, we used mass spectrometry sequencing, gene inactivation, and recombinant proteins to identify Streptococcus pyogenes protein Human gp340, also known as DMBT1 (deleted in malignant brain tumors 1), belongs to the innate immune protein family of scavenger receptor cysteine-rich (SRCR) 2 proteins, all of which contain one or more evolutionarily conserved SRCR domain linked to other conserved protein domains (1, 2). Many of these proteins serve as pattern recognition receptors for innate immunity. gp340 is expressed by epithelial cells and cells of the immune system, and its expression is up-regulated after inflammatory stimuli (3, 4). It inhibits bacterial invasion to epithelial cells and the secretion of proinflammatory cytokines (5-7).Thus, it appears to be an important mediator of host immune responses to various microbes and was recently linked to Crohn disease, a human inflammatory bowel disease (8). gp340 is also found in human secretions like tears and saliva, and the salivary form has long been known as salivary agglutinin, which is an important molecule in oral biofilm formation and is suggested to have a role in dental caries development (9 -12). The mechanisms of gp340 action in these different biological contexts are not known. Common to all scavenger receptors, the ligand repertoire of gp340 is wide; it binds many different types of bacteria as well as viruses (10,13,14). The wide ligand recognition pattern of scavenger receptors is thought to be based on the recognition of common microbial structures, such as lipopolysaccharides and lipoteichoic acids, but in the case of gp340, specific bacterial surface proteins are reported to be involved in the interactions characterized (15-18). Because the importance of gp340/salivary agglutinin in the oral environment has been evident for a long time, most of our knowledge of gp340-microbial interactions is from studies with oral bacteria. For example, viridans streptococci, such as Streptococcus mutans and Streptococcus gordonii, interact with saliva gp340 via their surface proteins AgI/II and the sialic acid-binding Hsa or GspB adhesin. In these interactions, gp340 shows a peculiar fluid phase versus surfaceadsorbed behavior, as evidenced by AgI/II polypeptides primarily mediating aggregation of bacteria by fluid phase gp340, whereas the Hsa adhesin primarily mediates adhesion of S. gordonii to surface-bound gp340 (18)...

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Section: Discussionmentioning

confidence: 99%

Leucine-rich Repeats of Bacterial Surface Proteins Serve as Common Pattern Recognition Motifs of Human Scavenger Receptor gp340

Loimaranta¹,

Hytönen

Pulliainen

et al. 2009

Journal of Biological Chemistry

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“…46,47 However, the importance of the TLR-mediated response during P gingivalismediated periodontal disease is unknown. Studies using Mycobacterium avium and Haemophilus influenzae support the proposition that bacterial infection leads to increased expression of TLRs 12,13 and that these TLRs play a role in further innate immune sensing during Crohn's disease and tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Recognition of Invasive Bacteria Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice

et al. 2004

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Background— Infectious diseases have emerged as potential risk factors for cardiovascular disease (CVD). Epidemiological studies support a connection between periodontal disease, a chronic inflammatory disease of the supporting tissues of the teeth, and CVD. Methods and Results— To directly test the connection between periodontal disease and atherosclerosis, apoE −/− mice were orally challenged with the periodontal disease pathogen Porphyromonas gingivalis or an invasion-impaired P gingivalis fimbriae-deficient mutant (FimA−). Both wild-type P gingivalis and the FimA− mutant were detected in blood and aortic arch tissue of apoE −/− mice by PCR after challenge. ApoE −/− mice challenged with wild-type P gingivalis presented with increased atherosclerotic plaque and expressed the innate immune response markers Toll-like receptor (TLR)-2 and TLR-4 in aortic tissue. Despite detection of the FimA− mutant in the blood and in aortic arch tissue, apoE −/− mice challenged with the FimA− mutant did not present with periodontal disease, upregulation of TLRs, or accelerated atherosclerosis. Furthermore, we demonstrate that immunization to control P gingivalis -elicited periodontal disease concomitantly prevents P gingivalis -accelerated atherosclerosis. Conclusions— We conclude that invasive P gingivalis accelerates atherosclerosis.

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“…It is thought that these PRRs function as TLR-associated co-receptors that detect microbial pathogens or components thereof and present them to TLRs for activation of signaling pathways (19,21). In our efforts to determine the PRRs and the mechanisms involved in innate immune recognition of P. gingivalis fimbriae, we have found that CD14 directly binds fimbriae (22) and mediates their ability to stimulate TLR2-dependent TNF-␣ release (14,23). The ␤ 2 integrin CD11b/CD18 is also involved in P. gingivalis fimbriainduced cell activation (23), although it does not constitutively recognize this bacterial molecule (22).…”

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confidence: 99%

“…The multifunctional adhesive capacity of P. gingivalis fimbriae may result from versatile structural motifs, which in turn may offer pattern recognition substrate for the innate host defense. Indeed pattern recognition receptors (PRRs) 2 of the innate immune system can detect the presence of fimbriae and respond by inducing release of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) (13)(14)(15).…”

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confidence: 99%

Peptide Mapping of Bacterial Fimbrial Epitopes Interacting with Pattern Recognition Receptors

Hajishengallis

Ratti

Harokopakis

2005

Journal of Biological Chemistry

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The fimbriae of the oral pathogen Porphyromonas gingivalis induce Toll-like receptor 2 (TLR2)-dependent macrophage activation upon their recognition by CD14 and the ␤ 2 integrin CD11b/ CD18. To map functional epitopes of fimbriae that interact with these pattern recognition receptors (PRRs), we examined 20 synthetic peptides covering the entire length of the 41-kDa fimbrillin subunit. Using direct or competitive inhibition assays for receptor binding or cell activation, the CD14 binding activity of fimbriae was localized to residues 69 -90 and was essential for TLR2-dependent cytokine induction. The CD11b/CD18 binding activity of fimbriae was localized to two neighboring epitopes defined by residues 166 -185 and 206 -225. Unlike epitope 69 -90 that constitutively bound CD14, the CD11b/CD18 binding activity of epitopes 166 -185 and 206 -225 was inducible by integrin activators. The CD11b/CD18 binding activity played a contributory role to TLR2-dependent induction of tumor necrosis factor-␣ by fimbriae but was involved in specific down-regulation of interleukin-12. Cell activation by a combination of fimbrillin peptides corresponding to the CD14 and CD11b/CD18 binding activities resulted in higher tumor necrosis factor-␣ responses than would be expected from a simply additive effect, attributable to CD14-dependent inside-out signaling leading to enhanced binding interactions with CD11b/CD18. These data suggest that P. gingivalis fimbriae display a modular structure that interacts through discrete epitopes and in a regulated mode with distinct PRRs, which in turn differentially modulate the state of cell activation. Elucidation of pathogen interactions with PRRs at the molecular level may glean insight into host defense mechanisms as well as into microbial strategies that subvert innate immunity.Porphyromonas gingivalis is a Gram-negative bacterium that has been strongly associated with periodontal disease (1) and has more recently been implicated in systemic inflammatory conditions such as atherosclerosis (2-4). Studies in animal models of periodontitis or atherosclerosis have established the fimbriae (filamentous appendages on the cell surface) of P. gingivalis as a major virulence factor of this pathogen (5, 6). In vitro mechanistic studies have shown that fimbriae display adhesive properties that enable P. gingivalis to bind diverse extracellular substrates (7,8) or to interact with a variety of cell types (9 -12). The multifunctional adhesive capacity of P. gingivalis fimbriae may result from versatile structural motifs, which in turn may offer pattern recognition substrate for the innate host defense. Indeed pattern recognition receptors (PRRs) 2 of the innate immune system can detect the presence of fimbriae and respond by inducing release of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) (13-15).Monocytes/macrophages constitute a major source of TNF-␣ production, and their number increases in periodontal inflammation compared with healthy periodontal tissue (16,17). These cells express mu...

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Dependence of Bacterial Protein Adhesins on Toll-Like Receptors for Proinflammatory Cytokine Induction

Cited by 82 publications

References 57 publications

Leucine-rich Repeats of Bacterial Surface Proteins Serve as Common Pattern Recognition Motifs of Human Scavenger Receptor gp340

Leucine-rich Repeats of Bacterial Surface Proteins Serve as Common Pattern Recognition Motifs of Human Scavenger Receptor gp340

Innate Immune Recognition of Invasive Bacteria Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice

Peptide Mapping of Bacterial Fimbrial Epitopes Interacting with Pattern Recognition Receptors

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