scholarly journals A novel sialic acid-binding adhesin present in multiple species contributes to the pathogenesis of Infective endocarditis

2020 ◽  
Author(s):  
Meztlli O. Gaytán ◽  
Anirudh K. Singh ◽  
Shireen A. Woodiga ◽  
Surina A. Patel ◽  
Seon-Sook An ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Infective Endocarditis ◽  
Therapeutic Target ◽  
Heart Valves ◽  
Bacterial Species ◽  
Rabbit Model ◽  
Host Factors ◽  
Dependent Manner ◽  
Streptococcus Oralis ◽  
Sialic Acid Binding

AbstractBacterial binding to platelets is a key step in the development of infective endocarditis (IE). Sialic acid, a common terminal carbohydrate on host glycans, is the major receptor for streptococci on platelets. So far, all defined interactions between streptococci and sialic acid on platelets are mediated by serine rich repeat proteins (SRRPs). However, we identified Streptococcus oralis subsp. oralis IE-isolates that bind sialic acid but lack SRRPs. In addition to binding sialic acid, some SRRP-negative isolates also bind the cryptic receptor β-1,4-linked galactose through a yet unknown mechanism. Using comparative genomics, we identified a novel sialic acid-binding adhesin, here named AsaA (associated with sialic acid adhesion A), present in IE-isolates lacking SRRPs. We demonstrated that S. oralis subsp. oralis AsaA is required for binding to platelets in a sialic acid-dependent manner. AsaA comprises a non-repeat region (NRR), consisting of a FIVAR/CBM and two Siglec-like and Unique domains, followed by 31 DUF1542 domains. When recombinantly expressed, Siglec-like and Unique domains competitively inhibited binding of S. oralis subsp. oralis and directly interacted with sialic acid on platelets. We further demonstrated that AsaA impacts the pathogenesis of S. oralis subsp. oralis in a rabbit model of IE. Additionally, we found AsaA orthologues in other IE-causing species and demonstrated that the NRR of AsaA from Gemella haemolysans blocked binding of S. oralis subsp. oralis, suggesting that AsaA contributes to the pathogenesis of multiple IE-causing species. Finally, our findings provide evidence that sialic acid is a key factor for bacterial-platelets interactions in a broader range of species than previously appreciated, highlighting its potential as a therapeutic target.Authors summaryInfective endocarditis (IE) is typically a bacterial infection of the heart valves that causes high mortality. Infective endocarditis can affect people with preexisting lesions on their heart valves (Subacute-IE). These lesions contain platelets and other host factors to which bacteria can bind. Growth of bacteria and accumulation of host factors results in heart failure. Therefore, the ability of bacteria to bind platelets is key to the development of IE. Here, we identified a novel bacterial protein, AsaA, which helps bacteria bind to platelets and contributes to the development of disease. Although this virulence factor was characterized in Streptococcus oralis, a leading cause of IE, we demonstrated that AsaA is also present in several other IE-causing bacterial species and is likely relevant to their ability to cause disease. We showed that AsaA binds to sialic acid, a terminal sugar present on platelets, thereby demonstrating that sialic acid serves as a receptor for a wider range of IE-causing bacteria than previously appreciated, highlighting its potential as a therapeutic target.

scholarly journals A novel sialic acid-binding adhesin present in multiple species contributes to the pathogenesis of Infective endocarditis

2021 ◽  
Vol 17 (1) ◽  
pp. e1009222
Author(s):  
Meztlli O. Gaytán ◽  
Anirudh K. Singh ◽  
Shireen A. Woodiga ◽  
Surina A. Patel ◽  
Seon-Sook An ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Infective Endocarditis ◽  
Rabbit Model ◽  
Dependent Manner ◽  
Bacterial Binding ◽  
Repeat Proteins ◽  
Streptococcus Oralis ◽  
Sialic Acid Binding ◽  
Key Factor ◽  
Multiple Species

Bacterial binding to platelets is a key step in the development of infective endocarditis (IE). Sialic acid, a common terminal carbohydrate on host glycans, is the major receptor for streptococci on platelets. So far, all defined interactions between streptococci and sialic acid on platelets are mediated by serine-rich repeat proteins (SRRPs). However, we identified Streptococcus oralis subsp. oralis IE-isolates that bind sialic acid but lack SRRPs. In addition to binding sialic acid, some SRRP- isolates also bind the cryptic receptor β-1,4-linked galactose through a yet unknown mechanism. Using comparative genomics, we identified a novel sialic acid-binding adhesin, here named AsaA (associated with sialic acid adhesion A), present in IE-isolates lacking SRRPs. We demonstrated that S. oralis subsp. oralis AsaA is required for binding to platelets in a sialic acid-dependent manner. AsaA comprises a non-repeat region (NRR), consisting of a FIVAR/CBM and two Siglec-like and Unique domains, followed by 31 DUF1542 domains. When recombinantly expressed, Siglec-like and Unique domains competitively inhibited binding of S. oralis subsp. oralis and directly interacted with sialic acid on platelets. We further demonstrated that AsaA impacts the pathogenesis of S. oralis subsp. oralis in a rabbit model of IE. Additionally, we found AsaA orthologues in other IE-causing species and demonstrated that the NRR of AsaA from Gemella haemolysans blocked binding of S. oralis subsp. oralis, suggesting that AsaA contributes to the pathogenesis of multiple IE-causing species. Finally, our findings provide evidence that sialic acid is a key factor for bacterial-platelets interactions in a broader range of species than previously appreciated, highlighting its potential as a therapeutic target.

scholarly journals Streptococcus oralis subsp. dentisani Produces Monolateral Serine-Rich Repeat Protein Fibrils, One of Which Contributes to Saliva Binding via Sialic Acid

2019 ◽  
Vol 87 (10) ◽  
Author(s):  
Allen Ronis ◽  
Kenneth Brockman ◽  
Anirudh K. Singh ◽  
Meztlli O. Gaytán ◽  
Alexander Wong ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Infective Endocarditis ◽  
Structural Similarity ◽  
Carbohydrate Binding ◽  
Interspecies Interactions ◽  
Content Type ◽  
Streptococcus Oralis ◽  
Bacterial Adhesins ◽  
Protein Fibrils ◽  
Sialic Acid Binding

ABSTRACT Our studies reveal that the oral colonizer and cause of infective endocarditis Streptococcus oralis subsp. dentisani displays a striking monolateral distribution of surface fibrils. Furthermore, our data suggest that these fibrils impact the structure of adherent bacterial chains. Mutagenesis studies indicate that these fibrils are dependent on three serine-rich repeat proteins (SRRPs), here named fibril-associated protein A (FapA), FapB, and FapC, and that each SRRP forms a different fibril with a distinct distribution. SRRPs are a family of bacterial adhesins that have diverse roles in adhesion and that can bind to different receptors through modular nonrepeat region domains. Amino acid sequence and predicted structural similarity searches using the nonrepeat regions suggested that FapA may contribute to interspecies interactions, that FapA and FapB may contribute to intraspecies interactions, and that FapC may contribute to sialic acid binding. We demonstrate that a fapC mutant was significantly reduced in binding to saliva. We confirmed a role for FapC in sialic acid binding by demonstrating that the parental strain was significantly reduced in adhesion upon addition of a recombinantly expressed, sialic acid-specific, carbohydrate binding module, while the fapC mutant was not reduced. However, mutation of a residue previously shown to be essential for sialic acid binding did not decrease bacterial adhesion, leaving the precise mechanism of FapC-mediated adhesion to sialic acid to be defined. We also demonstrate that the presence of any one of the SRRPs is sufficient for efficient biofilm formation. Similar structures were observed on all infective endocarditis isolates examined, suggesting that this distribution is a conserved feature of this S. oralis subspecies.

scholarly journals Role of Neuraminidase-Producing Bacteria in Exposing Cryptic Carbohydrate Receptors forStreptococcus gordoniiAdherence

2018 ◽  
Vol 86 (7) ◽  
pp. e00068-18 ◽  
Author(s):  
Alex Wong ◽  
Margaret A. Grau ◽  
Anirudh K. Singh ◽  
Shireen A. Woodiga ◽  
Samantha J. King
Keyword(s):  
Sialic Acid ◽  
Oral Cavity ◽  
Bacterial Species ◽  
Dependent Manner ◽  
Neuraminidase Treatment ◽  
Content Type ◽  
Oral Epithelial Cells ◽  
Oral Environment ◽  
Oral Epithelial

ABSTRACTStreptococcus gordoniiis an early colonizer of the oral cavity. Although a variety ofS. gordoniiadherence mechanisms have been described, current dogma is that the major receptor forS. gordoniiis sialic acid. However, as many bacterial species in the oral cavity produce neuraminidase that can cleave terminal sialic acid, it is unclear whetherS. gordoniirelies on sialic acid for adherence to oral surfaces or if this species has developed alternative binding strategies. Previous studies have examined adherence to immobilized glycoconjugates and identified binding to additional glycans, but no prior studies have defined the contribution of these different glycan structures in adherence to oral epithelial cells. We determined that the majority ofS. gordoniistrains tested did not rely on sialic acid for efficient adherence. In fact, adherence of some strains was significantly increased following neuraminidase treatment. Further investigation of representative strains that do not rely on sialic acid for adherence revealed binding not only to sialic acid via the serine-rich repeat protein GspB but also to β-1,4-linked galactose. Adherence to this carbohydrate occurs via an unknown adhesin distinct from those utilized byStreptococcus oralisandStreptococcus pneumoniae. Demonstrating the potential biological relevance of binding to this cryptic receptor, we established thatS. oralisincreasesS. gordoniiadherence in a neuraminidase-dependent manner. These data suggest thatS. gordoniihas evolved to simultaneously utilize both terminal and cryptic receptors in response to the production of neuraminidase by other species in the oral environment.

scholarly journals Virulence factors in streptococcal infective endocarditis

2005 ◽  
Vol 26 (3) ◽  
pp. 114
Author(s):  
Derek W S Harty
Keyword(s):  
Infective Endocarditis ◽  
Heart Valves ◽  
Blood Stream ◽  
Mutans Streptococci ◽  
Oral Streptococci ◽  
Streptococcus Anginosus ◽  
Streptococcus Oralis ◽  
Causative Agents ◽  
Life Threatening ◽  
Micro Organisms

Infective endocarditis (IE) is a life threatening, endovascular infection occurring when bacteria enter the blood stream and adhere to heart valves. Mortality rates remain in the range of 11-27%. The most common infecting micro-organisms are now the staphylococci (44%) although streptococci (31%) and particularly the oral streptococci (21%) are still major causative agents. Many different oral streptococci have been isolated from IE cases, the most common being Streptococcus sanguinis, Streptococcus oralis, Streptococcus gordonii, Streptococcus mitis, Streptococcus anginosus group and mutans streptococci.

scholarly journals Fibrinogen-InducedStreptococcus mutansBiofilm Formation and Adherence to Endothelial Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Telma Blanca Lombardo Bedran ◽  
Jabrane Azelmat ◽  
Denise Palomari Spolidorio ◽  
Daniel Grenier
Keyword(s):  
Endothelial Cells ◽  
Infective Endocarditis ◽  
Biofilm Formation ◽  
Bacterial Species ◽  
Bactericidal Effect ◽  
Dependent Manner ◽  
Bacterial Cells ◽  
Human Fibrinogen ◽  
Polystyrene Support ◽  
The Impact

Streptococcus mutans, the predominant bacterial species associated with dental caries, can enter the bloodstream and cause infective endocarditis. The aim of this study was to investigateS. mutansbiofilm formation and adherence to endothelial cells induced by human fibrinogen. The putative mechanism by which biofilm formation is induced as well as the impact of fibrinogen onS. mutansresistance to penicillin was also evaluated. Bovine plasma dose dependently induced biofilm formation byS. mutans. Of the various plasma proteins tested, only fibrinogen promoted the formation of biofilm in a dose-dependent manner. Scanning electron microscopy observations revealed the presence of complex aggregates of bacterial cells firmly attached to the polystyrene support.S. mutansin biofilms induced by the presence of fibrinogen was markedly resistant to the bactericidal effect of penicillin. Fibrinogen also significantly increased the adherence ofS. mutansto endothelial cells. NeitherS. mutanscells nor culture supernatants converted fibrinogen into fibrin. However, fibrinogen is specifically bound to the cell surface ofS. mutansand may act as a bridging molecule to mediate biofilm formation. In conclusion, our study identified a new mechanism promotingS. mutansbiofilm formation and adherence to endothelial cells which may contribute to infective endocarditis.

scholarly journals Binding of the Streptococcus gordonii DL1 Surface Protein Hsa to the Host Cell Membrane Glycoproteins CD11b, CD43, and CD50

2008 ◽  
Vol 76 (10) ◽  
pp. 4686-4691 ◽  
Author(s):  
Yumiko Urano-Tashiro ◽  
Ayako Yajima ◽  
Eizo Takashima ◽  
Yukihiro Takahashi ◽  
Kiyoshi Konishi
Keyword(s):  
Sialic Acid ◽  
Infective Endocarditis ◽  
Surface Protein ◽  
Oral Streptococci ◽  
Streptococcus Gordonii ◽  
Membrane Glycoproteins ◽  
Host Cell Membrane ◽  
Neuraminidase Treatment ◽  
Sialic Acid Binding

ABSTRACTInfective endocarditis is frequently attributed to oral streptococci. The mechanisms of pathogenesis, however, are not well understood, although interaction between streptococci and phagocytes are thought to be very important. A highly expressed surface component ofStreptococcus gordonii, Hsa, which has sialic acid-binding activity, contributes to infective endocarditis in vivo. In the present study, we found thatS. gordoniiDL1 binds to HL-60 cells differentiated into monocytes, granulocytes, and macrophages. Using a glutathioneS-transferase (GST) fusion to the NR2 domain, which is the sialic acid-binding region of Hsa, we confirmed that the Hsa NR2 domain also binds to differentiated HL-60 cells. To identify which sialoglycoproteins on the surface of differentiated HL-60 cells are receptors for Hsa, intrinsic membrane proteins were assessed by bacterial overlay and far-Western blotting.S. gordoniiDL1 adhered to 100- to 150-kDa proteins, a reaction that was abolished by neuraminidase treatment. These sialoglycoproteins were identified as CD11b, CD43, and CD50 by GST pull-down assay and immunoprecipitation with each specific monoclonal antibody. These data suggest thatS. gordoniiDL1 Hsa specifically binds to three glycoproteins as receptors and that this interaction may be the initial bacterial binding step in infective endocarditis by oral streptococci.

scholarly journals Contribution of Sialic Acid-Binding Adhesin to Pathogenesis of Experimental Endocarditis Caused by Streptococcus gordonii DL1

2006 ◽  
Vol 74 (1) ◽  
pp. 740-743 ◽  
Author(s):  
Yukihiro Takahashi ◽  
Eizo Takashima ◽  
Kisaki Shimazu ◽  
Hisao Yagishita ◽  
Takaaki Aoba ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Aortic Valve ◽  
Infection Rate ◽  
Inflammatory Reaction ◽  
Heart Valves ◽  
Streptococcus Gordonii ◽  
Gene Encoding ◽  
Insertional Mutation ◽  
Sialic Acid Binding

ABSTRACT An insertional mutation in hsa, the gene encoding the sialic acid-binding adhesin of Streptococcus gordonii DL1, resulted in a significant reduction of the infection rate of the organism and an inflammatory reaction in the rat aortic valve with experimental endocarditis, suggesting that the adhesin contributes to the infectivity of the organism for heart valves.

scholarly journals Streptococcus oralis Neuraminidase Modulates Adherence to Multiple Carbohydrates on Platelets

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Anirudh K. Singh ◽  
Shireen A. Woodiga ◽  
Margaret A. Grau ◽  
Samantha J. King
Keyword(s):  
Sialic Acid ◽  
Bacterial Species ◽  
Carbohydrate Binding ◽  
Content Type ◽  
Terminal Sialic Acid ◽  
Bacterial Binding ◽  
Streptococcus Oralis ◽  
Glycan Receptors ◽  
First Time ◽  
Surface Carbohydrates

ABSTRACT Adherence to host surfaces is often mediated by bacterial binding to surface carbohydrates. Although it is widely appreciated that some bacterial species express glycosidases, previous studies have not considered whether bacteria bind to multiple carbohydrates within host glycans as they are modified by bacterial glycosidases. Streptococcus oralis is a leading cause of subacute infective endocarditis. Binding to platelets is a critical step in disease; however, the mechanisms utilized by S. oralis remain largely undefined. Studies revealed that S. oralis, like Streptococcus gordonii and Streptococcus sanguinis, binds platelets via terminal sialic acid. However, unlike those organisms, S. oralis produces a neuraminidase, NanA, which cleaves terminal sialic acid. Further studies revealed that following NanA-dependent removal of terminal sialic acid, S. oralis bound exposed β-1,4-linked galactose. Adherence to both these carbohydrates required Fap1, the S. oralis member of the serine-rich repeat protein (SRRP) family of adhesins. Mutation of a conserved residue required for sialic acid binding by other SRRPs significantly reduced platelet binding, supporting the hypothesis that Fap1 binds this carbohydrate. The mechanism by which Fap1 contributes to β-1,4-linked galactose binding remains to be defined; however, binding may occur via additional domains of unknown function within the nonrepeat region, one of which shares some similarity with a carbohydrate binding module. This study is the first demonstration that an SRRP is required to bind β-1,4-linked galactose and the first time that one of these adhesins has been shown to be required for binding of multiple glycan receptors.

scholarly journals Molecular recognition of sialoglycans by streptococcal Siglec-like adhesins: toward the shape of specific inhibitors

2021 ◽  
Author(s):  
Cristina Di Carluccio ◽  
Alba Silipo ◽  
Roberta Marchetti ◽  
Barbara Ben ◽  
Koichi Fukase ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Infective Endocarditis ◽  
Molecular Recognition ◽  
Oral Cavity ◽  
Commensal Bacteria ◽  
Streptococcus Gordonii ◽  
Healthy Individuals ◽  
Sialic Acid Binding ◽  
Specific Inhibitors

Streptococcus gordonii and sanguinis, commensal bacteria present in the oral cavity of healthy individuals, upon entry into the bloodstream can become pathogenic, causing infective endocarditis (IE). Sialic acid-binding serine-rich repeat...

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