Attachment is the source of all suffering: delineating mechanisms of adhesion in Staphylococcus aureus endocarditis.

Abstract

Infective endocarditis (IE) is a life-threatening infection and the reported incidence is on the rise worldwide. Historically, cardiac valvulopathy due to rheumatic heart disease was the predominant risk factor for IE, and the majority of these infections were caused by streptococci from the oral or gastrointestinal tract. However, more recently, Staphylococcus aureus has emerged as a major causative organism in industrialized countries. IE due to S. aureus tends to have a rapid and aggressive course, with valve destruction and large vegetations with a propensity to embolize, resulting in haematogenous dissemination to distant sites. Despite improvements in diagnostic and treatment modalities, the mortality and complications associated with S. aureus IE remain high, and mostly unaltered over the last two decades. The ability of microorganisms to form vegetations on endocardial surfaces depends on a combination of host and pathogen factors, and a deeper understanding of this process is critical for developing novel preventive and management strategies. In vitro experiments and animal models have provided significant insight into the mechanisms by which certain bacteria cause IE. Local endothelial damage caused by turbulent blood flow from underlying structural heart disease or the presence of an intracardiac device may trigger the deposition of platelets, fibrin, and other matrix ligands. This results in the formation of a sterile vegetation (also known as non-bacterial thrombotic endocarditis or NBTE). Sterile vegetations can also develop from systemic conditions that cause endothelial inflammation, leading to the expression of receptors that promote local deposition of fibronectin. These findings have been described in patients with degenerative valvular disease, malignancy, connective tissue disorders, hypercoagulable states, sepsis, intravenous drug use, and burns. When bacteria with tropism for cardiac endothelium are introduced into the bloodstream, through the skin or breakdown of the mucosal surface barrier, these bloodborne pathogens may adhere to and colonize these sterile vegetations. A number of genusand species-specific virulence factors determine the affinity with which each microorganism adheres to these formations. Staphylococcus aureus, in particular, has the ability not only to colonize damaged or inflamed endothelium but also to evade the immune response, produce biofilm, and replicate intracellularly to ensure its survival. Moreover, direct adhesion to endothelial cells by S. aureus, without pre-formed sterile vegetations or inflammation, has also been described, and is thought to be the mechanism explaining the complications associated with IE such as metastatic embolization. Following colonization, progression to infection is determined by a number of bacterial and host factors. Once infection is established, vegetation growth and tissue destruction are promoted by further platelet–fibrin deposition and bacterial replication. Historically, in vivo studies of IE pathogenesis and treatment have mostly utilized animal models subjected to valvular damage due to mechanical injury. In these animal models, injury to cardiac valves is induced by placing a catheter across the aortic valve, via the carotid artery. The injured tissue is then exposed to the intravenous administration of a bacterial load at 24–72 h post-catheterization. Inflammation and deposition of bacteria on the traumatized tissue containing platelet–thrombi aggregates can be observed postbacterial injection. These animal models have led to a better understanding of the phases involved in bacterial adhesion, virulence factors, and the study of antibacterial agents to treat IE. In recent years, the incidence of IE in ‘normal’ valves has increased, representing now nearly a quarter of all cases. The most commonly isolated pathogen in the majority of these cases is S. aureus. It is hypothesized that endothelial inflammation, rather than mechanical damage, is the predisposing factor leading to vegetation formation in these cases. There are no existing animal models to elucidate the