Defining mechanisms of binding utilized by the infective endocarditis pathogen Streptococcus mitis
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Date
2024-05
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The Ohio State University
Abstract
Streptococcus mitis is an oral commensal and a common cause of subacute infective endocarditis (IE), a bacterial infection exhibiting an upward trend in mortality and hospitalizations. Subacute IE often occurs when viridans group streptococci, commonly found in the oral cavity, enter the bloodstream and bind to damaged heart endothelium. These bacteria specifically bind to platelets, via sialic acid, that accumulate at the site of damage. Platelet binding is a key step in the development of IE and a potential therapeutic target. Until recently all described mechanisms of sialic acid binding were mediated by serine rich repeat proteins (SRRPs) such as Fap1 produced by Streptococcus oralis. However, our group identified a novel sialic acid-binding protein, AsaA, in S. oralis strains that lack Fap1, suggesting additional mechanisms of sialic acid binding may exist. Although S. mitis is a common cause of IE, no mechanisms of adhesion have been defined. To start filling this gap in knowledge, we examined the distribution of orthologs of fap1 and asaA across 20 genome sequenced S. mitis strains. What was initially thought to be an ortholog of asaA, was actually two distinct genes producing putative adhesins, AsaA and AsaB, differing in the frequency of repeat domains and genomic location A fourth putative sialic acid-binding adhesin, Rib, containing a different repeat domain, was identified by predicted structural conservation of sialic acid-binding domains. Further analysis suggests asaA and rib evolved from asaB. While the genes encoding MonX and AsaA are mutually exclusive in both S. oralis and S. mitis, some strains are predicted to produce one of these adhesins and AsaB and/or Rib. These data suggest some S. mitis strains produce novel sialic acid-binding adhesins and multiple adhesins may contribute to platelet binding. To start investigating how S. mitis binds sialic acid, we selected B6, which contains asaB and monX and efficiently binds sialic acid on platelets. We have generated a monX mutant and the construct to inactivate asaB. Once all mutants have been obtained, platelet binding assays with single and double mutants will be performed. The long-term goal of these studies is to gain a comprehensive understanding of all mechanisms of platelet binding. As binding is a key step in IE pathogenesis, our hope is that these studies will allow the development of broadly effective therapeutic strategies.
Description
Second place in Health Under the Microscope at the Denman Undergraduate Research Forum
Keywords
Sialic acid adhesins, Streptococcus mitis, Infective endocarditis, platelet binding