Sialic Acid-Binding Protein
            <i>Sp</i>
            2CBMTD Protects Mice against Lethal Challenge with Emerging Influenza A (H7N9) Virus

Govorkova, Elena A.; Baranovich, Tatiana; Marathe, Bindumadhav M.; Yang, Lei; Taylor, Margaret; Webster, Robert G.; Taylor, G.L.; Connaris, Helen

doi:10.1128/aac.04431-14

Cited by 10 publications

(13 citation statements)

References 26 publications

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“…Further experiments to determine the NanA binding partner(s) are ongoing. The Sp CBM domain, in addition to showing promise as a bio-therapeutic against respiratory pathogens [ 12 , 22 ], is a potential drug target and may be exploited as part of a combinatorial drug design approach to inhibit NanA attachment and catalysis.…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of the carbohydrate-binding module of NanA sialidase, a pneumococcal virulence factor

et al. 2015

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BackgroundStreptococcus pneumoniae Neuraminidase A (NanA) is a multi-domain protein anchored to the bacterial surface. Upstream of the catalytic domain of NanA is a domain that conforms to the sialic acid-recognising CBM40 family of the CAZY (carbohydrate-active enzymes) database. This domain has been identified to play a critical role in allowing the bacterium to promote adhesion and invasion of human brain microvascular endothelial cells, and hence may play a key role in promoting bacterial meningitis. In addition, the CBM40 domain has also been reported to activate host chemokines and neutrophil recruitment during infection.ResultsCrystal structures of both apo- and holo- forms of the NanA CBM40 domain (residues 121 to 305), have been determined to 1.8 Å resolution. The domain shares the fold of other CBM40 domains that are associated with sialidases. When in complex with α2,3- or α2,6-sialyllactose, the domain is shown to interact only with the terminal sialic acid. Significantly, a deep acidic pocket adjacent to the sialic acid-binding site is identified, which is occupied by a lysine from a symmetry-related molecule in the crystal. This pocket is adjacent to a region that is predicted to be involved in protein-protein interactions.ConclusionsThe structural data provide the details of linkage-independent sialyllactose binding by NanA CBM40 and reveal striking surface features that may hold the key to recognition of binding partners on the host cell surface. The structure also suggests that small molecules or sialic acid analogues could be developed to fill the acidic pocket and hence provide a new therapeutic avenue against meningitis caused by S. pneumoniae.

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Section: Discussionmentioning

confidence: 99%

Structural characterization of the carbohydrate-binding module of NanA sialidase, a pneumococcal virulence factor

et al. 2015

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“…Such changes in binding affinity are conferred by selection of beneficial HA1 mutations affecting receptor specificity, antigenicity, and/or functional compatibility with the NA protein. It is worth noting, that since one of the new therapeutic strategies to control influenza is masking SA receptors [ 32 , 33 ] from the epithelial surface, such approach might result in enhanced viral receptor specificity to the masked receptors. We consider that the tracking of such changes on the HA1 molecule is important for prediction of possible evolutionary changes of the pandemic H1N1 viruses toward a potentially more virulent form.…”

Section: Discussionmentioning

confidence: 99%

The use of plant lectins to regulate H1N1 influenza A virus receptor binding activity

et al. 2018

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We applied an in vitro selection approach using two different plant lectins that bind to α2,3- or α2,6-linked sialic acids to determine which genetic changes of the A/California/04/09 (H1N1) virus alter hemagglutinin (HA) receptor binding toward α2,3- or α2,6-linked glycans. Consecutive passages of the A/California/04/09 virus with or without lectins in human lung epithelial Calu-3 cells led to development of three HA1 amino acid substitutions, N129D, G155E, and S183P, and one mutation in the neuraminidase (NA), G201E. The S183P mutation significantly increased binding to several α2,6 SA-linked glycans, including YDS, 6′SL(N), and 6-Su-6′SLN, compared to the wild-type virus (↑3.6-fold, P < 0.05). Two other HA1 mutations, N129D and G155E, were sufficient to significantly increase binding to α2,6-linked glycans, 6′SLN and 6-Su-6′SLN, compared to S183P (↑4.1-fold, P < 0.05). These HA1 mutations also increased binding affinity for 3′SLN glycan compared to the wild-type virus as measured by Biacore surface plasmon resonance method. In addition, the HA1 N129D and HA1 G155E substitutions were identified as antigenic mutations. Furthermore, the G201E mutation in NA reduced the NA enzyme activity (↓2.3-fold). These findings demonstrate that the A/California/04/09 (H1N1) virus can acquire enhanced receptor affinity for both α2,3- and α2,6-linked sialic receptors under lectin-induced selective pressure. Such changes in binding affinity are conferred by selection of beneficial HA1 mutations that affect receptor specificity, antigenicity, and/or functional compatibility with the NA protein.

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“…High molecular weight kininogen (HMWK) is precurosor for bradykinin, which is an important mediator of endothelial permeability. Hantavirus infected endothelial cells induce increased cleavage of HMWK with increased bradykinin and vascular permeability [ 49 ]. Increased nasal secretions have been correlated with increased glandular bradykinin in experimental infection of adult humans with IAV H1N1 [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Respiratory Mucosal Proteome Quantification in Human Influenza Infections

et al. 2016

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Respiratory influenza virus infections represent a serious threat to human health. Underlying medical conditions and genetic make-up predispose some influenza patients to more severe forms of disease. To date, only a few studies have been performed in patients to correlate a selected group of cytokines and chemokines with influenza infection. Therefore, we evaluated the potential of a novel multiplex micro-proteomics technology, SOMAscan, to quantify proteins in the respiratory mucosa of influenza A and B infected individuals. The analysis included but was not limited to quantification of cytokines and chemokines detected in previous studies. SOMAscan quantified more than 1,000 secreted proteins in small nasal wash volumes from infected and healthy individuals. Our results illustrate the utility of micro-proteomic technology for analysis of proteins in small volumes of respiratory mucosal samples. Furthermore, when we compared nasal wash samples from influenza-infected patients with viral load ≥ 28 and increased IL-6 and CXCL10 to healthy controls, we identified 162 differentially-expressed proteins between the two groups. This number greatly exceeds the number of DEPs identified in previous studies in human influenza patients. Most of the identified proteins were associated with the host immune response to infection, and changes in protein levels of 151 of the DEPs were significantly correlated with viral load. Most important, SOMAscan identified differentially expressed proteins heretofore not associated with respiratory influenza infection in humans. Our study is the first report for the use of SOMAscan to screen nasal secretions. It establishes a precedent for micro-proteomic quantification of proteins that reflect ongoing response to respiratory infection.

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Sialic Acid-Binding Protein Sp 2CBMTD Protects Mice against Lethal Challenge with Emerging Influenza A (H7N9) Virus

Cited by 10 publications

References 26 publications

Structural characterization of the carbohydrate-binding module of NanA sialidase, a pneumococcal virulence factor

Structural characterization of the carbohydrate-binding module of NanA sialidase, a pneumococcal virulence factor

The use of plant lectins to regulate H1N1 influenza A virus receptor binding activity

Respiratory Mucosal Proteome Quantification in Human Influenza Infections

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