Marginal role of von Willebrand factor-binding protein and coagulase in the initiation of endocarditis in rats with catheter-induced aortic vegetations

Abstract

Staphylococcus aureus is the leading cause of infective endocarditis (IE). While the role of S. aureus cell-wall associated protein clumping factor A (ClfA) in promoting IE has been already demonstrated, that of the secreted plasma-clotting factors staphylocoagulase (Coa) and von Willebrand factor-binding protein (vWbp) has not yet been elucidated. We investigated the role of Coa and vWbp in IE initiation in rats with catheter-induced aortic vegetations, using Lactococcus lactis expressing coa, vWbp, clfA or vWbp/clfA, and S. aureus Newman Δcoa, ΔvWbp, ΔclfA or Δcoa/ ΔvWbp/ΔclfA mutants. vWbp-expression increased L. lactis valve infection compared to parent and coa-expressing strains (incidence: 62%, versus 0% and 13%, respectively; P < 0.01). Likewise, expression of clfA increased L. lactis infectivity (incidence: 80%), which was not further affected by co-expression of vWbp. In symmetry, deletion of the coa or vWbp genes in S. aureus did not decrease infectivity (incidence: 68 and 64%, respectively) whereas deletion of clfA did decrease valve infection (incidence: 45%; P = 0.03 versus parent), which was not further affected by the triple deletion Δcoa/ΔvWbp/ΔclfA (incidence: 36%; P > 0.05 versus ΔclfA mutant). Coa does not support the initial colonization of IE (in L. lactis) without other key virulence factors and vWbp contributes to initiation of IE (in L. lactis) but is marginal in the present of ClfA.

Multimodal imaging of bacterial-host interface in mice and piglets with Staphylococcus aureus endocarditis

“…We detected decreased thrombin in mouse endocarditis vegetations after treatment with antibodies that neutralize SC and vWBp. In line with studies using knockout bacteria (22), we observed that vegetations still evolved and mice succumbed eventually; nevertheless, antibody treatment prolonged survival, whereas DAB-VT680XL signal decreased in the lesions and innate immune cells invaded bacterial colonies. Because of the differences between the mouse and human immune systems and prior failures to translate antibody therapeutics for S. aureus infections from mouse to man (23), it is unclear whether the introduced antibody neutralization of SC and vWBp will work in patients until this has been tested and whether such therapy is efficient if initiated during later disease stages.…”

Infective Endocarditis in High-Income Countries

“…Bacterial adhesion constitutes one of the fundamental stages in the pathophysiological process of infective endocarditis. Once the endothelial lesion is established, bacterial adhesion is favored, initially by the release of inflammatory cytokines associated with tissue factors and a second time by the expression of fibronectin, which leads to the formation of a thrombus composed of platelets and fibrin [ 116 , 117 , 118 ]. We learned that the common pathogens responsible for endocarditis colonize the valves with pre-existing sterile vegetations or valves in which minimal endothelial lesions occur.…”

“…The inflammatory response established in the endothelium is orchestrated by the production of cytokines, integrins, and tissue factors, which in turn attract monocytes and platelets with associated production of fibronectin, due to the effect induced by chemokines. These structures allow the bacteria to attack and the latter further activate the inflammatory cascade which offers, through their incorporation, protection by the host’s defenses [ 117 , 118 ] ( Figure 7 ).…”

Pathophysiology of Infective Endocarditis in High-Income Countries

“…This bridge facilitates the recognition between pathogen and host cell leading to subsequent cell integration. [162][163][164][165] Although the osteoblasts evidenced high expression of α5β1-integrin and fibronectin and the bacteria disclosed a high affinity to adhere to osteoblasts, Niemann et al demonstrated, through internalization tests and immunofluorescence microscopy, that S. aureus was less swallowed. in osteoblasts compared to epithelial cells.…”