Signalling or binding: the role of the platelet-activating factor receptor in invasive pneumococcal disease

Iovino, Federico; Brouwer, Matthijs C.; Beek, Diederik van de; Molema, Grietje; Bijlsma, Jetta J. E.

doi:10.1111/cmi.12129

Cited by 42 publications

(42 citation statements)

References 72 publications

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“…In addition, poly immunoglobulin receptor (pIgR), which transports immunoglobulins across mucosal epithelium, and platelet endothelial cell adhesion molecule-1 (PECAM-1), involved in leukocyte migration and angiogenesis in the endothelium, have also been found to be utilized by pneumococci for endothelium adhesion and invasion [62,63]. It has been proposed that pneumococcal infection in itself may upregulate pIgR and PECAM-1 expression via a PAFR-mediated signalling mechanism [64]. Pneumococcal cellular components, such as choline-binding proteins and pneumolysin, or PAF synthesized by the host innate immune response, are believed to mediate binding to PAFR.…”

Section: Central Nervous Systemmentioning

confidence: 99%

“…Pneumococcal cellular components, such as choline-binding proteins and pneumolysin, or PAF synthesized by the host innate immune response, are believed to mediate binding to PAFR. This interaction in turn stimulates multiple signal transduction pathways including phospholipase C, D, A2, mitogen-activated protein kinases (MAPKs) and the phosphatidylinositol-calcium second messenger system, thereby increasing the expression of pneumococcal adhesion receptors pIgR or PECAM-1 [64][65][66]. In addition, pneumococcal pilus-1 adhesin RrgA and pilus-2 adhesin PitB have been implicated in pneumococci-mediated adhesion and invasion of brain endothelial cells and respiratory epithelial cells [67][68][69].…”

Section: Central Nervous Systemmentioning

confidence: 99%

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Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

Shukla

Walters

et al. 2017

Microbiology

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Host surface receptors provide bacteria with a foothold from which to attach, colonize and, in some cases, invade tissue and elicit human disease. In this review, we discuss several key host receptors and cognate adhesins that function in bacterial pathogenesis. In particular, we examine the elevated expression of host surface receptors such as CEACAM-1, CEACAM-6, ICAM-1 and PAFR in response to specific stimuli. We explore how upregulated receptors, in turn, expose the host to a range of bacterial infections in the respiratory tract. It is apparent that exploitation of receptor induction for bacterial adherence is not unique to one body system, but is also observed in the central nervous, gastrointestinal and urogenital systems. Prokaryotic pathogens which utilize this mechanism for their infectivity include Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis and Escherichia coli. A number of approaches have been used, in both in vitro and in vivo experimental models, to inhibit bacterial attachment to temporally expressed host receptors. Some of these novel strategies may advance future targeted interventions for the prevention and treatment of bacterial disease.

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Section: Central Nervous Systemmentioning

confidence: 99%

Section: Central Nervous Systemmentioning

confidence: 99%

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

Shukla

Walters

et al. 2017

Microbiology

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“…The platelet-activating factor receptor (PAFR) is implicated in pneumococcal adhesion to endothelial cells [5], [6], [7]. In vitro blocking and transfection studies and most in vivo experiments using PAFR −/− mice clearly indicate that PAFR contributes to the development of invasive pneumococcal disease (IPD) [5], [6], [7], [8]. The question that still remains is whether S. pneumoniae binds directly to PAFR.…”

Section: Introductionmentioning

confidence: 99%

Streptococcus pneumoniae Interacts with pIgR Expressed by the Brain Microvascular Endothelium but Does Not Co-Localize with PAF Receptor

2014

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Streptococcus pneumoniae is thought to adhere to the blood-brain barrier (BBB) endothelium prior to causing meningitis. The platelet activating factor receptor (PAFR) has been implicated in this adhesion but there is a paucity of data demonstrating direct binding of the bacteria to PAFR. Additionally, studies that inhibit PAFR strongly suggest that alternative receptors for pneumococci are present on the endothelium. Therefore, we studied the roles of PAFR and pIgR, an established epithelial pneumococcal receptor, in pneumococcal adhesion to brain endothelial cells in vivo. Mice were intravenously infected with pneumococci and sacrificed at various time points before meningitis onset. Co-localization of bacteria with PAFR and pIgR was investigated using immunofluorescent analysis of the brain tissue. In vitro blocking with antibodies and incubation of pneumococci with endothelial cell lysates were used to further probe bacteria-receptor interaction. In vivo as well as in vitro pneumococci did not co-localize with PAFR. On the other hand the majority of S. pneumoniae co-localized with endothelial pIgR and pIgR blocking reduced pneumococcal adhesion to endothelial cells. Pneumococci physically interacted with pIgR in endothelial cell lysates. In conclusion, bacteria did not associate with PAFR, indicating an indirect role of PAFR in pneumococcal adhesion to endothelial cells. In contrast, pIgR on the BBB endothelium may represent a novel pneumococcal adhesion receptor.

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“…One receptor implicated in adherence is the PAF receptor, and its natural ligand, PAF, is structurally related to ChoP. The adherence of S. pneumoniae to cytokine-activated epithelial cells is reduced after PAF receptor antagonist treatment (7), and the role of the PAF receptor in invasive pneumococcal diseases has been reviewed recently (45). The PAF receptor is induced after S. pneumoniae infection (8,46), which suggests that ChoP upregulation in S. pneumoniae is advantageous for anchoring to the respiratory epithelia before invasive infection.…”

Section: Discussionmentioning

confidence: 99%

Impact of the glpQ2 Gene on Virulence in a Streptococcus pneumoniae Serotype 19A Sequence Type 320 Strain

et al. 2015

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dGlycerophosphodiester phosphodiesterase (GlpQ) metabolizes glycerophosphorylcholine from the lung epithelium to produce free choline, which is transformed into phosphorylcholine and presented on the surfaces of many respiratory pathogens. Two orthologs of glpQ genes are found in Streptococcus pneumoniae: glpQ, with a membrane motif, is widespread in pneumococci, whereas glpQ2, which shares high similarity with glpQ in Haemophilus influenzae and Mycoplasma pneumoniae, is present only in S. pneumoniae serotype 3, 6B, 19A, and 19F strains. Recently, serotype 19A has emerged as an epidemiological etiology associated with invasive pneumococcal diseases. Thus, we investigated the pathophysiological role of glpQ2 in a serotype 19A sequence type 320 (19AST320) strain, which was the prevalent sequence type in 19A associated with severe pneumonia and invasive pneumococcal disease in pediatric patients. Mutations in glpQ2 reduced phosphorylcholine expression and the anchorage of cholinebinding proteins to the pneumococcal surface during the exponential phase, where the mutants exhibited reduced autolysis and lower natural transformation abilities than the parent strain. The deletion of glpQ2 also decreased the adherence and cytotoxicity to human lung epithelial cell lines, whereas these functions were indistinguishable from those of the wild type in complementation strains. In a murine respiratory tract infection model, glpQ2 was important for nasopharynx and lung colonization. Furthermore, infection with a glpQ2 mutant decreased the severity of pneumonia compared with the parent strain, and glpQ2 gene complementation restored the inflammation level. Therefore, glpQ2 enhances surface phosphorylcholine expression in S. pneumoniae 19AST320 during the exponential phase, which contributes to the severity of pneumonia by promoting adherence and host cell cytotoxicity. P hosphorylcholine (ChoP) is a unique feature of many respiratory bacterial species. In the cell wall of pneumococci, ChoP is a component of lipoteichoic acid and teichoic acid that anchors various choline-binding proteins (CBPs) via the choline-binding domain on the pneumococcal surface (1). These CBPs regulate autolysis and the natural transformation of Streptococcus pneumoniae (2), as well as promoting the internalization of pneumococci into pharyngeal epithelial cells to escape phagocytes (3-6).The structure of ChoP resembles that of the platelet-activating factor (PAF), and thus, ChoP on S. pneumoniae can interact directly with the host PAF receptor (7) and allow S. pneumoniae to transit the epithelial and endothelial layers during invasion (8). The conjugation between ChoP and the PAF receptor is important for pneumococcal sequestration during immune clearance and systemic dissemination, since mice deficient in PAF receptor or treated with PAF receptor antagonist abolish pneumococcal pneumonia progression to cause sepsis and meningitis (9).The presentation of ChoP on the bacterial surface requires an available choline source in the environment (10, 11). Fre...

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Signalling or binding: the role of the platelet-activating factor receptor in invasive pneumococcal disease

Cited by 42 publications

References 72 publications

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

Streptococcus pneumoniae Interacts with pIgR Expressed by the Brain Microvascular Endothelium but Does Not Co-Localize with PAF Receptor

Impact of the glpQ2 Gene on Virulence in a Streptococcus pneumoniae Serotype 19A Sequence Type 320 Strain

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