In order to produce infection, enterococci must be able to colonize host tissues, resist the host's non-specific and immune defense mechanisms and produce pathological changes. Enterococcal virulence factors can contribute to enterococcal disease in different ways; by enhancing colonization, adherence and invasion of host tissues, by modulation of the host immunity, and by inducing pathological changes in the host associated with increased severity of infection .
With regard to colonization of host tissues, adherence assays have shown that enterococci can attach to intestinal and urinary tract epithelial cells and heart cells by means of adhesins expressed on the bacterial surface. The expression of these adhesins by enterococci has further been shown to be affected by bacterial growth conditions. In addition, the adherence of E. faecalis to renal tubular cells in vitro is enhanced if the organisms produce aggregation substance, a proteinaceous surface material that aggregates donor and recipient bacteria to facilitate plasmid transfer. Bacterial growth conditions also affect the interaction of enterococci with polymorphonuclear leucocytes (PMNLs), with serum-grown organisms showing less association with PMNLs than organisms grown in broth. Efficient killing of enterococci by PMNLs in vitro requires the presence of serum complement proteins and is enhanced by anti-enterococcal antibodies.
In addition to the hardiness of the genus, other components have been implicated as important factors in the sequence of events that lead to clinical human disease. Acid tolerance, mediated by any stimulus that causes an increase in proton pump activity, is thought to allow enterococci to survive passage through the stomach prior to colonization of the lower bowel.
Aggregation substance is thought to play a role in the translocation of enterococci from the intestinal lumen to the mesenteric lymph nodes, liver, and spleen. Enterococci produce a number of factors that may be associated with pathological changes in the host. Both sex pheromones and plasmid-encoded pheromone inhibitors produced by E. faecalis are chemotactic for PMNLs in vitro, and may mediate, at least in part, the inflammatory response often associated with enterococcal infection. E. faecalis may also produce a plasmid-encoded haemolysin, which is associated with increased severity of infection. In addition, enterococci are capable of inducing platelet aggregation and tissue factor-dependent fibrin production, which may be relevant to the pathogenesis of enterococcal endocarditis. Although questions concerning the pathogenicity of enterococci remain unanswered, it is clear that we are now beginning to understand the mechanisms by which this important group of microorganisms produces disease, although additional mechanisms are thought to also contribute. Another factor thought to be involved in adhesion is enterococcal surface protein (Esp), which has also been demonstrated to aid in the formation of a bacterial biofilm, and contributes to a mouse model of urinary tract infection.
Colonization, adherence and invasion of host tissues
Bacterial adherence to host tissues is a crucial first step in the infection process. Adhesins that promote binding to eukaryotic receptors on mucosal surfaces would be expected to play a critical role in maintenance of colonization. Without specific means of attachment, enterococci would likely be eliminated by bulk flow of luminal contents through normal intestinal motility. Adherence through surface-exposed adhesins to epithelial cells, endothelial cells, leukocytes, or extracellular matrix is generally a first step in infection. A close association is likely to exist between enterococci and its host, or the organism would be eliminated due to normal intestinal motility. Many infection-derived enterococcal isolates were found to be clonal, indicating nosocomial transmission. Moreover, a number of studies have documented patient colonization following hospital admission, and have shown that colonization with multiple resistant strains is a predisposing factor for subsequent infection. To colonize the lower bowel, enterococci must survive transit through the low pH of the stomach. Several studies have examined the acid tolerance of E. faecalis demonstrated that exposure of E. faecalis to a sub-lethal pH (pH 4.8) for 15-30 minutes protected the organism from a normally lethal challenge at pH 3.2. From these studies, it is apparent that enterococci possess the ability to withstand the low gastric pH, which would facilitate colonization. This attribute may be critical in the ability of multi-drug resistant enterococcal strains to colonize the intestinal tract and cause hospital ward outbreaks. Whether infection-derived enterococcal isolates show enhanced acid tolerance is yet to be determined. Therapy with antibiotics possessing little anti-enterococcal activity is a key predisposing factor leading to enterococcal colonization and infection.
Studies in mice with antibiotic- induced intestinal E. faecalis overgrowth demonstrated that organisms can adhere to epithelial surfaces of the ileum, cecum, and colon. These same studies showed that enterococci possess the ability to translocate from the intestinal lumen to the mesenteric lymph nodes, liver, and spleen.
As prior antibiotic therapy appears to be a predisposing factor for enterococcal infection, antibiotic-induced intestinal overgrowth by E. faecalis, followed by translocation of the organism into the circulation may offer one explanation for bacteremias of unknown etiology. The mechanisms responsible for enterococcal translocation are not clearly defined. One hypothesis is that enterococci are phagocytosed by tissue macrophages or intestinal epithelial cells, and are transported across the intestinal wall to the underlying lymphatic system. Failure to kill the phagocytosed organisms could then lead to systemic spread.
Modulation of the host immunity
For pathogens breaching mucosal or skin barriers and adhering to host tissues or cells, infection can develop only if other defenses are neutralized, avoided, or restricted. Professional phagocytes such as neutrophils, monocytes, and macrophages provide nonspecific, but powerful, host defenses against pathogens of all types. Neutrophils, in particular, migrate efficiently to sites of infection in response to chemotactic signals, use complement and antibody for pathogen recognition, and kill ingested organisms by oxidative and nonoxidative mechanisms. E. faecalis must overcome the clearance functions of the host system to successfully cause infection. PMNs are a critical component of the human host response against bacterial infections. Invading bacteria may be coated by complement proteins or specific antibodies and subsequently phagocytosed and killed by PMNs. This process of coating of bacteria with complement proteins or antibodies to enhance phagocytosis is called opsonization. Studies involving the role of antibodies and complement in the phagocytic killing of enterococci revealed that PMNs mediated killing depended primarily on complement activation by either the classical or the alternative pathway.
Antibodies to E. faecalis enhanced the PMNs mediated killing, however they were not essential as different studies showed efficient killing also in the presence of serum without gamma globulins . Although antibodies to enterococci are found in humans with enterococcal infections, studies on the efficacy of antibodies to E. faecalis in the prevention of infections are quite contradicting.
Huebner et al. found prophylactic and therapeutic efficacy of antibodies to a capsular polysaccharide in a mouse infective model. In addition, the role of antibodies to the surface protein aggregation substance (Agg) in prevention of endocarditis is underscored by the absence of host antibodies specific for the Agg during the formation of endocardial vegetation. Thereby the bacteria are protected from the influence of the antibodies.
However, another study on the efficacy of antibodies to Agg in the prevention of endocarditis in a rabbit model did not show any protection. E. faecalis has developed different strategies to overcome the immune response.
Weeks et al. reported a prolonged intracellular survival of enterococci for up to 72 h in mouse peritoneal macrophages. This property might contribute to the pathogenesis of infections in the way that the enterococci migrate to distant sites in the body and be protected from antimicrobial therapy within the macrophage. In line with these findings are the results of other investigations reporting that Agg promotes direct, opsonin-independent binding of E. faecalis to PMNs and that through this opsonin-independent binding E. faecalis was able to survive inside different phagocytes.
Another study showed that strains expressing gelatinase, cytolysin, or Agg were not more resistant to neutrophil mediated killing, but the in vitro assays were performed under circumstances that might not support expression of these traits or mimic the in vivo situation. The structure of the Esp with multiple repeat motifs in the encoding gene might be important in the immune evasion of infecting E. faecalis.
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