Acid Exposure Stimulates the Adherence of<i>Streptococcus pneumoniae</i>to Cultured Human Airway Epithelial Cells

Ishizuka, Satoshi; Yamaya, Mutsuo; Suzuki, Tomoko; Nakayama, Katsutoshi; Kamanaka, Masahito; Ida, Shiroh; Sekizawa, Kiyohisa; Sasaki, Hidetada

doi:10.1165/ajrcmb.24.4.4248

Cited by 47 publications

(51 citation statements)

References 39 publications

(63 reference statements)

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“…Although this pattern of expression suggests a bias in the gut for providing mechanisms for inducing immune responses against gram-negative bacteria, receptors, such as PAF-R, can bind both gram-negative and gram-positive bacteria (11,20,22). Low levels of TLR-2 expression by intestinal epithelial cells, including on Caco-2 cells, has also previously been reported and these cells were found to be broadly unresponsive to a range of gram-positive ligands (15).…”

Section: Discussionmentioning

confidence: 78%

Microbial Pattern Recognition Receptors Mediate M-Cell Uptake of a Gram-Negative Bacterium

et al. 2006

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The receptors involved in the sampling of particulate microbial antigens by the gut are largely unknown. Here we demonstrate for the first time in an in vitro M-cell model and in situ in isolated murine intestinal segments that the receptors TLR-4, PAF-R, and ␣5␤1 integrin are all involved in mediating bacterial uptake associated with transcytosis. The pattern of expression of TLR-4 and ␣5␤1 integrin differed between M cells and enterocytes. There was increased apical expression of TLR-4 in M-cell cultures, and it was present on the apical surface of murine M cells but not enterocytes in situ. In contrast, PAF-R was expressed equally by both cell types in vitro and was abundantly expressed throughout the intestinal epithelium. Inhibition of TLR-4 and PAF-R, but not TLR-2, reduced gram-negative bacterial uptake by both cell types, whereas inhibition of the apically expressed ␣5␤1 integrin significantly reduced the ability of M cells to translocate bacteria. Hence, the involvement of each receptor was dependent not only on differences in the level of receptor expression but the cellular localization. Using bacteria that had mutations that affected the bacterial lipooligosaccharide structure indicated that the oligosaccharide moiety was important in bacterial uptake. Taken together, the data suggest that pathogen-associated molecular pattern interactions with pattern recognition receptors are key factors in M-cell recognition of intestinal antigens for mucosal immune priming.The sampling of particulate microbial antigen by epithelial cells of the gastrointestinal tract resulting in stimulation of the mucosal immune system has long been thought of as a specific receptor-driven event. These receptors are considered to be specific to the microfold (M) cells that are found within the follicle-associated epithelia (FAE) that overlie the mucosal immune inductive tissue of the Peyer's patches of the intestine (6,16,17). Researchers have demonstrated that interactions between pathogenic bacteria and the gut epithelia rely on several pathways, such as receptor-mediated uptake as demonstrated by Yersinia enterocolytica invasin-␤1 integrin interactions (8); type III secretion systems, such as the translocated intimin receptor (Tir)-dependent disruption of the intestinal epithelia by enteropathogenic Escherichia coli (13); and the paracellular invasion strategy used by Campylobacter enteritis (10). However, the species-specific variability of potential Mcell receptors (12) and a failure to find receptors that are specific to human M cells that are not present elsewhere on the gut lining has thwarted research efforts to target mucosal antigen uptake for the induction of mucosal immune responses.Prokaryotes contain molecular motifs that are unique to microorganisms. These motifs, known as common microbial pathogen-associated molecular patterns (PAMPs), are recognized by the innate immune system through pattern recognition receptors (PRRs), either through direct receptor-bacterial ligand or endogenous adaptor-bacterial molecule i...

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Section: Discussionmentioning

confidence: 78%

Microbial Pattern Recognition Receptors Mediate M-Cell Uptake of a Gram-Negative Bacterium

et al. 2006

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“…Such an increase in intracellular GSH induces a reduction in inflammatory cytokine release through inhibition of NFkB activation (Aoki et al, 1996;Antonicelli et al, 2002;Biswas & Rahman, 2009). A previous study reported that the pyrrolidine derivative pyrrolidine dithiocarbamate, an NFkB inhibitor, reduces acid-induced S. pneumoniae adherence to A549 cells via inhibition of PAFR induction (Ishizuka et al, 2001). Together, these findings suggest that the reduction in PAFR expression in epithelial cells treated with S-CMC is attributable to suppression of NF-kB activation by GSH flux.…”

Section: Resultsmentioning

confidence: 99%

S-Carboxymethylcysteine inhibits adherence of Streptococcus pneumoniae to human alveolar epithelial cells

Sumitomo

Nakata

Yamaguchi

et al. 2012

Journal of Medical Microbiology

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Streptococcus pneumoniae is a major pathogen of respiratory infections that utilizes platelet-activating factor receptor (PAFR) for firm adherence to host cells. The mucolytic agent S-carboxymethylcysteine (S-CMC) has been shown to exert inhibitory effects against infection by several respiratory pathogens including S. pneumoniae in vitro and in vivo. Moreover, clinical studies have implicated the benefits of S-CMC in preventing exacerbation of chronic obstructive pulmonary disease, which is considered to be related to respiratory infections. In this study, to assess whether the potency of S-CMC is attributable to inhibition of pneumococcal adherence to host cells, an alveolar epithelial cell line stimulated with interleukin-1a was used as a model of inflamed epithelial cells. Despite upregulation of PAFR by inflammatory activation, treatment with S-CMC efficiently inhibited pneumococcal adherence to host epithelial cells. In order to gain insight into the inhibitory mechanism, the effects of S-CMC on PAFR expression were also investigated. Following treatment with S-CMC, PAFR expression was reduced at both mRNA and post-transcriptional levels. Interestingly, S-CMC was also effective in inhibiting pneumococcal adherence to cells transfected with PAFR small interfering RNAs. These results indicate S-CMC as a probable inhibitor targeting numerous epithelial receptors that interact with S. pneumoniae. INTRODUCTIONStreptococcus pneumoniae is a major cause of communityacquired pneumonia, sinusitis and otitis media, and is also associated with acute exacerbations of chronic obstructive pulmonary disease (COPD) (Miravitlles et al., 1999). Among the numerous pneumococcal adherence mechanisms responsible for causing diseases, phosphorylcholine binds specifically to platelet-activating factor receptor (PAFR) expressed on the surface of airway epithelial cells (Cundell et al., 1995(Cundell et al., , 1996Fischer, 2000). Previous in vivo experiments demonstrated that PAFR-deficient mice were less likely to develop invasive disease or had improved host defence during pneumococcal infection (Rijneveld et al., 2004). Therefore, the interaction between PAFR and phosphorylcholine plays a crucial role in the pathogenesis of pneumococcal disease.The mucolytic agent S-carboxymethylcysteine (S-CMC) is widely used as an expectorant in Europe and Asia for the treatment of respiratory diseases with phlegm production. Administration of S-CMC is also effective for COPD patients in terms of reductions in symptom exacerbation and improvements in quality of life (Zheng et al., 2008). It is generally accepted that bacterial colonization is a determinant for COPD exacerbation. Hence, it has been speculated that the potency of S-CMC against respiratory pathogens, including S. pneumoniae (Cakan et al., 2003;Suer et al., 2008), Moraxella catarrhalis (Zheng et al., 1999) and non-typable Haemophilus influenzae (Ndour et al., 2001), contributes to a reduction in episodes of respiratory infection in COPD patients. However, the mechanism by which S-C...

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“…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. In addition, ChoP facilitates the anchorage of CBPs on pneumococci.…”

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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Acid Exposure Stimulates the Adherence ofStreptococcus pneumoniaeto Cultured Human Airway Epithelial Cells

Cited by 47 publications

References 39 publications

Microbial Pattern Recognition Receptors Mediate M-Cell Uptake of a Gram-Negative Bacterium

Microbial Pattern Recognition Receptors Mediate M-Cell Uptake of a Gram-Negative Bacterium

S-Carboxymethylcysteine inhibits adherence of Streptococcus pneumoniae to human alveolar epithelial cells

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

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