A novel sialic acid-binding adhesin present in multiple species contributes to the pathogenesis of Infective endocarditis
Authors: Gaytán Meztlli O. , Singh Anirudh K. , Woodiga Shireen A. , Patel Surina A. , An Seon-Sook , de León Arturo Vera-Ponce , McGrath Sean , Miller Anthony R. , Bush Jocelyn M. , van der Linden Mark , Magrini Vincent , Wilson Richard K. , Kitten Todd , King Samantha J. 
Published: July 2020

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 identifiedStreptococcus oralissubsp.oralisIE-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 withsialic acidadhesion A), present in IE-isolates lacking SRRPs. We demonstrated thatS. oralissubsp.oralisAsaA 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 ofS. oralissubsp.oralisand directly interacted with sialic acid on platelets. We further demonstrated that AsaA impacts the pathogenesis ofS. oralissubsp.oralisin a rabbit model of IE. Additionally, we found AsaA orthologues in other IE-causing species and demonstrated that the NRR of AsaA fromGemella haemolysansblocked binding ofS. oralissubsp.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 summary

Infective 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 inStreptococcus 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.