Glucosyltransferases of Viridans Streptococci Are Modulins of Interleukin-6 Induction in Infective Endocarditis

Abstract

The glucosyltransferases (GTFs) of viridans streptococci, common pathogens of infective endocarditis, are extracellular proteins that convert sucrose into exopolysaccharides and glucans. GTFs B, C, and D of Streptococcus mutans are modulins that induce, in vitro and in vivo, the production of cytokines, in particular interleukin-6 (IL-6), from monocytes. The roles of S. mutans GTFs in infectivity and inflammation in situ were tested in a rat experimental model of endocarditis. No significant differences in infectivity, in terms of 95% infective dose and densities of bacteria inside vegetations, were observed between laboratory strain GS-5 and two clinical isolates or isogenic mutant NHS1DD, defective in the expression of GTFs. In aortic valves and surrounding tissues, IL-6 was detected by Western blots and immunostaining 24 h after GS-5 infection, was maintained over 72 h, and was followed by production of tumor necrosis factor alpha but not IL-1␤. Animals infected with NHS1DD showed markedly lower levels of IL-6 (less than 5% of that of parental GS-5-infected rats), while tumor necrosis factor alpha was unaffected. In contrast, animals infected with NHR1DD, another isogenic mutant expressing only GtfB, showed a much smaller reduction (down to 56%). These results suggest that GTFs are specific modulins that act during acute inflammation, inducing IL-6 from endothelial cells surrounding the infected valves without affecting bacterial colonization in vegetations, and that IL-6 might persist in chronic inflammation in endocarditis.

Inflammatory Response in Infective Endocarditis

“…It was found that levels of IL-6 and tumor necrosis factor alpha secreted from endothelial cells of mice infected by S. viridans strains were directly related to their GTFs expression (30). During the chronic stage of the disease, IL-6 production persists, but at that stage it may also originate from the monocytes (30). Another study showed that GTF was capable of inducing the expression of adhesion molecules and the release of IL-6 and plays an important role in the transition from neutrophil to monocyte recruitment in the early stages ofIE (31).…”

“…It was found that levels of IL-6 and tumor necrosis factor alpha secreted from endothelial cells of mice infected by S. viridans strains were directly related to their GTFs expression (30). During the chronic stage of the disease, IL-6 production persists, but at that stage it may also originate from the monocytes (30).…”

Endocarditis Pathogen Promotes Vegetation Formation by Inducing Intravascular Neutrophil Extracellular Traps Through Activated Platelets

“…Using GFP-tagged S mutans GS5 and the rat endocarditis model, 11,17 we previously demonstrated that bacterial biofilm embedded in aggregated platelets form a unique layered structure with unidentified interlayers of amorphous but wellorganized meshes interconnecting the bacteria-platelet layers inside the vegetation. 16 Confocal laser scanning microscopic analysis revealed the presence of extracellular DNA meshes intermixing with the bacteria biofilm inside the vegetation (Figure 1).…”

Molecular characterization of Streptococcus mutans strains isolated from the heart valve of an infective endocarditis patient

“…However, S. mutans strains lacking expression of all three types of GTF have also been isolated from infected heart valve tissues (Nomura et al, 2006), indicating that GTFs do not contribute directly to the virulence of S. mutans in IE. In contrast, Shun et al (2005) demonstrated that the survival rate of mice infected with an isogenic mutant strain lacking all three types of GTF was significantly lower than that of those infected with the parental strain as well as the uninfected control group.…”