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

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 ß-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.

Vessel-by-Vessel Computed Tomography Calcium Scoring of the Foot in Peripheral Artery Disease: Association with Patient-Level Factors.

Objective: Peripheral artery disease (PAD) is associated with increased risk of nonhealing ulcers, amputation, and mortality due to occlusive atherosclerotic plaques. Computed tomography (CT) imaging detects vascular calcification in PAD; however, quantitative vessel-by-vessel analysis of calcium burden in the feet of PAD patients has not been assessed. This study sought to perform quantitative analysis of vessel-specific calcium burden and examine the patient-level determinants of foot calcium burden in PAD patients. Approach: PAD patients (n = 41) were prospectively enrolled and underwent CT imaging of the lower extremities. Manual segmentation of the medial plantar, lateral plantar, and dorsalis pedis arteries was performed. CT image Hounsfield units (HUs) were obtained for each artery to quantify vessel-by-vessel calcium mass using a cutoff value of ≥130 HU. Univariate analyses were performed to evaluate patient-level determinants of calcium burden for each foot artery. STROBE guidelines were used for reporting of data. Results: Univariate analyses revealed that body mass index, diabetes mellitus (DM), and chronic kidney disease (CKD) were significant determinants of foot calcium burden in PAD patients. Image analysis demonstrated that PAD patients with DM had significantly higher calcium mass for the medial plantar (p = 0.005), lateral plantar (p = 0.039), and dorsalis pedis (p = 0.001) arteries compared with PAD patients without DM. Innovation: This is the first study to use CT imaging to quantify vessel-specific calcium burden in the feet of patients with PAD and evaluate the patient-level determinants of foot calcium burden in the setting of PAD. Conclusion: CT imaging quantifies vessel-specific calcification in the feet of PAD patients, which is exacerbated with concomitant DM, CKD, and/or obesity.