The ability to utilize mucin affects the regulation of virulence gene expression in<i>Streptococcus pneumoniae</i>

Yeşilkaya, Hasan; Manco, Sonia; Kadioglu, Aras; Terra, Vanessa S.; Andrew, Peter W.

doi:10.1111/j.1574-6968.2007.01003.x

Cited by 71 publications

(90 citation statements)

References 22 publications

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“…Neuraminidase activity of different pneumococcal isolates can differ greatly [30], for various reasons, such as the presence of one to three different neuraminidase genes [22] and NanA mosaicism that can influence enzyme activity [75]. Regardless of the underlying molecular mechanism, our study provides evidence that neuraminidase activity across a range of different pneumococcal isolates can be antagonized by the combination of α-NanA and α-NanBC mAbs in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 87%

“…Moreover, A549 cells are not multi-layered and do not produce mucus. This might eliminate an important source of sialic acid used for growth during infection [30]. However, in the absence of this major natural barrier the pneumococcus may more readily access underlying sugars and adhere to host cells.…”

Section: Discussionmentioning

confidence: 99%

“…NanA is required for pneumococcal growth on mucins (sialylated glycoproteins abundantly found in the respiratory tract) [30] and its expression is upregulated in the presence of lung cells [31]. By deglycosylating human serum components, NanA can interfere with C3 deposition on the pneumococcal surface and reduce opsonophagocytosis by human neutrophils [32].…”

Section: Introductionmentioning

confidence: 99%

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Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

et al. 2018

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Streptococcus pneumoniae isolates express up to three neuraminidases (sialidases), NanA, NanB and NanC, all of which cleave the terminal sialic acid of glycan-structures that decorate host cell surfaces. Most research has focused on the role of NanA with limited investigations evaluating the roles of all three neuraminidases in host-pathogen interactions. We generated two highly potent monoclonal antibodies (mAbs), one that blocks the enzymatic activity of NanA and one cross-neutralizing NanB and NanC. Total neuraminidase activity of clinical S. pneumoniae isolates could be inhibited by this mAb combination in enzymatic assays. To detect desialylation of cell surfaces by pneumococcal neuraminidases, primary human tracheal/bronchial mucocilial epithelial tissues were infected with S. pneumoniae and stained with peanut lectin. Simultaneous targeting of the neuraminidases was required to prevent desialylation, suggesting that inhibition of NanA alone is not sufficient to preserve terminal lung glycans. Importantly, we also found that all three neuraminidases increased the interaction of S. pneumoniae with human airway epithelial cells. Lectin-staining of lung tissues of mice pre-treated with mAbs before intranasal challenge with S. pneumoniae confirmed that both anti-NanA and anti-NanBC mAbs were required to effectively block desialylation of the respiratory epithelium in vivo. Despite this, no effect on survival, reduction in pulmonary bacterial load, or significant changes in cytokine responses were observed. This suggests that neuraminidases have no pivotal role in this murine pneumonia model that is induced by high bacterial challenge inocula and does not progress from colonization as it happens in the human host.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

et al. 2018

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“…First-strand cDNA synthesis was performed on approximately 1 g of DNase-treated total RNA, immediately after isolation, using 200 U of SuperScript II reverse transcriptase (Invitrogen, Paisley, United Kingdom) at 42°C for 55 min and random hexamers (52). cDNA (15 ng) was amplified in a 20-l reaction volume that contained 1ϫ SYBR green PCR master mix (Applied Biosystems, Foster City, CA) and 3 pmol of each primer (indicated with an "RTF" or "RTR" tag in Table 1).…”

Section: Construction Of Mutantsmentioning

confidence: 99%

“…The supernatant and the pellet were kept for the analysis of cytoplasmic and membrane proteins, respectively. The quality of fractionation was determined by assessing activities of lactate dehydrogenase, which is known have an intracellular localization, and neuraminidase, which is localized on the cell wall, in different fractions as described previously (17,52).…”

Section: Construction Of Mutantsmentioning

confidence: 99%

Streptococcus pneumoniae

Peter¹,

Klein²

2008

Principles and Practice of Pediatric Infectious Disease

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The pneumococcus obtains its energy from the metabolism of host glycosides. Therefore, efficient degradation of host glycoproteins is integral to pneumococcal virulence. In search of novel pneumococcal glycosidases, we characterized the Streptococcus pneumoniae strain D39 protein encoded by SPD_0065 and found that this gene encodes a ␤-galactosidase. The SPD_0065 recombinant protein released galactose from desialylated fetuin, which was used here as a model of glycoproteins found in vivo. A pneumococcal mutant with a mutation in SPD_0065 showed diminished ␤-galactosidase activity, exhibited an extended lag period in mucin-containing defined medium, and cleaved significantly less galactose than the parental strain during growth on mucin. As pneumococcal ␤-galactosidase activity had been previously attributed solely to SPD_0562 (bgaA), we evaluated the contribution of SPD_0065 and SPD_0562 to total ␤-galactosidase activity. Mutation of either gene significantly reduced enzymatic activity, but ␤-galactosidase activity in the double mutant, although significantly less than that in either of the single mutants, was not completely abolished. The expression of SPD_0065 in S. pneumoniae grown in mucin-containing medium or tissues harvested from infected animals was significantly upregulated compared to that in pneumococci from glucose-containing medium. The SPD_0065 mutant strain was found to be attenuated in virulence in a manner specific to the host tissue.Streptococcus pneumoniae is the leading cause of bacterial pneumonia, otitis media, bacterial meningitis, and septicemia (21). Furthermore, a high percentage of the population carries the bacterium in the nasopharynx, asymptomatically or as a prelude to disease (53). The upsurge in antibiotic-resistant strains and the search for new vaccines highlight the need to understand more completely the nature of pneumococcal virulence. A survey of pneumococcal virulence studies indicates a clear asymmetry in favor of research focusing on factors involved in attachment and damage to host tissues and in immune evasion (2,11,15,22,38). Although these studies have revealed useful information about pneumococcal virulence, there is a severe lack of knowledge on the basic physiology of S. pneumoniae, such that little information is available on how the pneumococcus fulfils its nutritional requirements for the generation of energy.Carbohydrates are the principal energy sources for the pneumococcus, and these must be obtained exclusively from its host (16). Although the pneumococcus is known to utilize a variety of free sugars through at least 14 sugar utilization operons (10), in the upper respiratory tract the concentration of free sugars is low (39). However, monosaccharides are copious within the structures of O-and N-linked oligosaccharides of glycoproteins, which are found predominantly in the structures of mucins (Fig. 1) and in circulatory glycoproteins, respectively. Previous studies have shown that the sequential deglycosylation of N-linked glycan structures by pneumococcal...

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Glycan‐metabolizing enzymes in microbe–host interactions: the Streptococcus pneumoniae paradigm

2018

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Streptococcus pneumoniae is a frequent colonizer of the upper airways; however, it is also an accomplished pathogen capable of causing life-threatening diseases. To colonize and cause invasive disease, this bacterium relies on a complex array of factors to mediate the host-bacterium interaction. The respiratory tract is rich in functionally important glycoconjugates that display a vast range of glycans, and, thus, a key component of the pneumococcus-host interaction involves an arsenal of bacterial carbohydrate-active enzymes to depolymerize these glycans and carbohydrate transporters to import the products. Through the destruction of host glycans, the glycan-specific metabolic machinery deployed by S. pneumoniae plays a variety of roles in the host-pathogen interaction. Here, we review the processing and metabolism of the major host-derived glycans, including N- and O-linked glycans, Lewis and blood group antigens, proteoglycans, and glycogen, as well as some dietary glycans. We discuss the role of these metabolic pathways in the S. pneumoniae-host interaction, speculate on the potential of key enzymes within these pathways as therapeutic targets, and relate S. pneumoniae as a model system to glycan processing in other microbial pathogens.

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The ability to utilize mucin affects the regulation of virulence gene expression inStreptococcus pneumoniae

Cited by 71 publications

References 22 publications

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

Streptococcus pneumoniae

Glycan‐metabolizing enzymes in microbe–host interactions: the Streptococcus pneumoniae paradigm

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