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Gaytán, Meztlli O.; Singh, Anirudh K.; Woodiga, Shireen A.; Patel, Surina A.; An, Seon-Sook; Vera-Ponce de León, Arturo; McGrath, Sean; Miller, Anthony R.; Bush, Jocelyn M.; van der Linden, Mark; Magrini, Vincent; Wilson, Richard K.; Kitten, Todd; King, Samantha J.

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

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  • Media type: E-Article
  • Title: A novel sialic acid-binding adhesin present in multiple species contributes to the pathogenesis of Infective endocarditis
  • Contributor: Gaytán, Meztlli O.; Singh, Anirudh K.; Woodiga, Shireen A.; Patel, Surina A.; An, Seon-Sook; Vera-Ponce de León, Arturo; McGrath, Sean; Miller, Anthony R.; Bush, Jocelyn M.; van der Linden, Mark; Magrini, Vincent; Wilson, Richard K.; Kitten, Todd; King, Samantha J.
  • imprint: Public Library of Science (PLoS), 2021
  • Published in: PLOS Pathogens
  • Language: English
  • DOI: 10.1371/journal.ppat.1009222
  • ISSN: 1553-7374
  • Keywords: Virology ; Genetics ; Molecular Biology ; Immunology ; Microbiology ; Parasitology
  • Origination:
  • Footnote:
  • Description: <jats:p>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 <jats:italic>Streptococcus oralis</jats:italic> subsp. <jats:italic>oralis</jats:italic> IE-isolates that bind sialic acid but lack SRRPs. In addition to binding sialic acid, some SRRP<jats:sup>-</jats:sup> 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 (<jats:underline>a</jats:underline>ssociated with <jats:underline>s</jats:underline>ialic acid <jats:underline>a</jats:underline>dhesion A), present in IE-isolates lacking SRRPs. We demonstrated that <jats:italic>S</jats:italic>. <jats:italic>oralis</jats:italic> subsp. <jats:italic>oralis</jats:italic> 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 <jats:italic>S</jats:italic>. <jats:italic>oralis</jats:italic> subsp. <jats:italic>oralis</jats:italic> and directly interacted with sialic acid on platelets. We further demonstrated that AsaA impacts the pathogenesis of <jats:italic>S</jats:italic>. <jats:italic>oralis</jats:italic> subsp. <jats:italic>oralis</jats:italic> in a rabbit model of IE. Additionally, we found AsaA orthologues in other IE-causing species and demonstrated that the NRR of AsaA from <jats:italic>Gemella haemolysans</jats:italic> blocked binding of <jats:italic>S</jats:italic>. <jats:italic>oralis</jats:italic> subsp. <jats:italic>oralis</jats:italic>, 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.</jats:p>
  • Access State: Open Access