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Abstract
Streptococcus sanguinis (S. sanguinis) is an abundant oral commensal which can cause disseminated human infection if it gains access to the bloodstream. The most important among these diseases is infective endocarditis (IE). While virulence phenotypes of S. sanguinis have been correlated to disease severity, genetic factors mediating these phenotypes, and contributing to pathogenesis are largely uncharacterized. In this report, we investigate the roles of 128 genes in virulence-related phenotypes of S. sanguinis and characterize the pathogenic potential of two selected mutants in a left-sided, native valve IE rabbit model. Assays determining the ability of our mutant strains to produce a biofilm, bind to and aggregate platelets, and adhere to or invade endothelial cells identified sixteen genes with novel association to these phenotypes. These results suggest the presence of many uncharacterized genes involved in IE pathogenesis which may be relevant for disease progression. Two mutants identified by the above screening process – SSA_1099, encoding an RTX-like protein, and mur2, encoding a peptidoglycan hydrolase – were subsequently evaluated in vivo. Wild type (WT) S. sanguinis reliably induced cardiac vegetations, while the SSA_1099 and mur2 mutants produced either no vegetation or vegetations of small size. Splenomegaly was reduced in both mutant strains compared to WT, while pathology of other distal organs was indistinguishable. Histopathology analyses suggest the cardiac lesions and vegetations in this model resemble those observed in humans. These data indicate that SSA_1099 and mur2 encode virulence factors in S. sanguinis which are integral to pathogenesis of IE.
Highlights
Streptococcus sanguinis (S. sanguinis) is a commensal organism important in promoting oral health but may become pathogenic if given the opportunity
Of importance is infective endocarditis (IE), which is an infection of the heart valves and/or endocardium, because the infection is associated with complications that include congestive heart failure, aneurysm and stroke (Mylonakis and Calderwood, 2001; Murdoch et al, 2009; DeSimone et al, 2015)
The first step in mutant construction was amplification of a kanamycinresistance gene fragment by polymerase chain reaction (PCR) that was flanked by 1,000 bp upstream and downstream of the open reading frame
Summary
Streptococcus sanguinis (S. sanguinis) is a commensal organism important in promoting oral health but may become pathogenic if given the opportunity. The oral cavity of humans is a rich environment providing a moist, warm niche for colonization by hundreds of different bacterial species that are typically harmless or beneficial to the oral health of humans. The most abundant of these bacterial species are those belonging to the genus Streptococcus. Within this environment, S. sanguinis, a primary colonizer of the tooth surface, provides benefits to the Streptococcal Virulence in Infective Endocarditis human host by protecting against the deleterious effects of another microorganism, S. mutans, the pathogen responsible for tooth decay and caries (Becker et al, 2002; Kreth et al, 2008). Despite improved diagnostic and treatment options, studies continue to report that endocarditis mortality rates range from 12 to 45% (Thuny et al, 2012; Bor et al, 2013)
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