Streptococcus pneumoniae early response genes to human lung epithelial cells

Song, Xin-Ming; Connor, Wayne; Hokamp, Karsten; Babiuk, Lorne A.; Potter, Andrew

doi:10.1186/1756-0500-1-64

Cited by 25 publications

(24 citation statements)

References 23 publications

(29 reference statements)

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“…We were able to demonstrate a difference in biofilm production after growth on human airway cells, which has been shown to induce nanA expression (27,39,46) and reduce capsule production (16). By selecting for organisms on human airway cells, we apparently mimicked a likely in vivo process in which encapsulated organisms that are able to avoid mucus entrapment and clearance gradually produce less capsule to facilitate epithelial attachment (20).…”

Section: Discussionmentioning

confidence: 97%

“…Streptococcus pneumoniae produces at least three distinct neuraminidases (41); NanA is the neuraminidase that is most active and most highly expressed at the transcriptional level (5,31), and it is conserved in all strains (21,24,41). Production of NanA can be detected in vivo, and its expression is upregulated upon interaction with host cells (27,39,46,58). The pneumococcal neuraminidase modifies host glycoconjugates, including immune defense proteins (22,23), and exposes potential binding receptors (3,26,28,54,55).…”

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confidence: 99%

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The NanA Neuraminidase of Streptococcus pneumoniae Is Involved in Biofilm Formation

et al. 2009

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Streptococcus pneumoniae remains a major cause of bacteremia, pneumonia, and otitis media despite vaccines and effective antibiotics. The neuraminidase of S. pneumoniae, which catalyzes the release of terminal sialic acid residues from glycoconjugates, is involved in host colonization in animal models of infection and may provide a novel target for preventing pneumococcal infection. We demonstrate that the S. pneumoniae neuraminidase (NanA) cleaves sialic acid and show that it is involved in biofilm formation, suggesting an additional role in pathogenesis, and that it shares this property with the neuraminidase of Pseudomonas aeruginosa even though we show that the two enzymes are phylogenetically divergent. Using an in vitro model of biofilm formation incorporating human airway epithelial cells, we demonstrate that small-molecule inhibitors of NanA block biofilm formation and may provide a novel target for preventative therapy. This work highlights the role played by the neuraminidase in pathogenesis and represents an important step in drug development for prevention of colonization of the respiratory tract by this important pathogen.

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

The NanA Neuraminidase of Streptococcus pneumoniae Is Involved in Biofilm Formation

et al. 2009

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“…An msmK mutant was significantly reduced in colonization when competed against its parent strain, suggesting that transport of at least one of the carbohydrate substrates is important during colonization. The exact contribution of each of the six transporters is currently unknown; however, previous data suggest that individual transporters vary in their contributions to both colonization and pathogenesis (4,11,16,23,29,37). While we did not assess the contribution of msmK to pathogenesis here, during the revision of the manuscript Tyx et al demonstrated a role for this gene in raffinose transport and pneumococcal pneumonia (40).…”

Section: Discussionmentioning

confidence: 99%

Identification of an ATPase, MsmK, Which Energizes Multiple Carbohydrate ABC Transporters in Streptococcus pneumoniae

et al. 2011

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Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and results in over 1 million deaths each year worldwide. Asymptomatic colonization of the airway precedes disease, and acquisition of carbohydrates from the host environment is necessary for bacterial survival. We previously demonstrated that S. pneumoniae cleaves sialic acid from human glycoconjugates to be used as a carbohydrate source. The satABC genes are required for growth and import of sialic acid. The satABC genes are predicted to encode components of an ABC transporter but not the ATPases essential to energize transport. As this subunit is essential, an ATPase must be encoded elsewhere in the genome. We identified msmK as a candidate based on similarity to other known carbohydrate ATPases. Recombinant MsmK hydrolyzed ATP, revealing that MsmK is an ATPase. An msmK mutant was reduced in growth on and transport of sialic acid, demonstrating that MsmK is the ATPase energizing the sialic acid transporter. In addition to satABC, S. pneumoniae contains five other loci that are predicted to encode CUT1 family carbohydrate ABC transporter components; each of these lacks a predicted ATPase. Data indicate that msmK is also required for growth on raffinose and maltotetraose, which are the substrates of two other characterized carbohydrate ABC transporters. Furthermore, an msmK mutant was reduced in airway colonization. Together, these data imply that in vivo, MsmK energizes multiple carbohydrate transporters in S. pneumoniae. This is the first demonstration of a shared ATPase in a pathogenic bacterium.

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“…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%

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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Streptococcus pneumoniae early response genes to human lung epithelial cells

Cited by 25 publications

References 23 publications

The NanA Neuraminidase of Streptococcus pneumoniae Is Involved in Biofilm Formation

The NanA Neuraminidase of Streptococcus pneumoniae Is Involved in Biofilm Formation

Identification of an ATPase, MsmK, Which Energizes Multiple Carbohydrate ABC Transporters in Streptococcus pneumoniae

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

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