Antibody response to the extracellular adherence protein (Eap) ofStaphylococcus aureusin healthy and infected individuals

Abstract

The extracellular adherence protein (Eap) from Staphylococcus aureus has been suggested as a vaccine candidate and for therapeutic use due to its immunomodulating and antiangiogenic properties; however, little is known about anti-Eap antibodies in humans. We determined anti-Eap antibody titers by enzyme-linked immunosorbent assay and Western blot and measured serum samples from 92 patients with proven S. aureus infections and 93 healthy controls. The functionality of antibodies was assessed by a phagocytosis assay using Eap-coated fluorescent microspheres. Antibodies were detected in all human samples, but not in mice. Patients showed significantly higher titers than controls [immunoglobulin M (IgM), P=0.007; IgG, P<0.0001]. Patients with deep or severe infections showed higher titers than those with superficial or mild disease. Eap alone was sufficient to promote phagocytosis by peripheral blood mononuclear cell and granulocytes that was moderately enhanced in the presence of human serum, but no correlation was found with the levels of anti-Eap antibodies. Anti-Eap antibodies are prevalent in all tested humans and correlate with the severity of S. aureus infection; however, they do not seem to provide protection against invasive infections. Before considering Eap for therapy or as a vaccine candidate, further studies are warranted to assess the impact of the interference between Eap and its specific antibodies.

The Extracellular Adherence Protein from Staphylococcus aureus Inhibits the Classical and Lectin Pathways of Complement by Blocking Formation of the C3 Proconvertase

“…Though the precise contributions of the CP and LP remain to be fully evaluated in each of these experimental systems, the consistent requirement of Eap for maximal levels of staphylococcal virulence in such studies is difficult to ignore. Moreover, the discovery that patients with demonstrated S. aureus infections present with high titers of anti-Eap antibodies (40), and that their titers of anti-Eap IgG correlate with the severity of infection (40), strongly suggests that Eap inhibition of the CP/LP is relevant to human disease as well. Along these lines, we have recently made the unexpected observation that all staphylococcal EAP domain-containing proteins (i.e.…”

“…Since many of these diseases are only poorly managed by current therapeutic regimens, our discovery of Eap as a potent CP/LP inhibitor raises the possibility that improved treatment of these conditions might come through further detailed study of Eap, its molecular interactions, and its ability to specifically attenuate CP/LP activity in vivo . Since high levels of anti-Eap antibodies are found in even healthy persons (40), direct use of Eap as a therapeutic is unlikely, due to greatly increased risk of immune complex disease. Thus, future work aimed at discovering either non-immunogenic peptides, peptidomimetics, or even small molecules that retain Eap-like inhibitory activities on the CP/LP will be necessary to exploit Eap's promise within these areas.…”

Staphylococcus aureus Extracellular Adherence Protein Triggers TNFα Release, Promoting Attachment to Endothelial Cells via Protein A

“…Cell wall components including peptidoglycan and lipoteichoic acid stimulate immune cells to produce TNFα, as do the secreted phenol-soluble modulins and delta toxin [36]–[38]. However, by contrast to the cytolysins, which are expressed in stationary phase, Eap is secreted during exponential-phase growth [21]. As such, the contribution of Eap to stimulation of TNFα production very likely occurs during a different phase of the infection to cytolytic toxins.…”

“…Despite this, a proportion of secreted Eap attaches to the staphylococcal cell wall and mediates attachment to, and invasion of, host cells via a bridging mechanism between host and microbe [14]–[18]. Eap expression in vivo has been demonstrated by RNA and Western-blot analyses of S. aureus wound infections, as well as the detection of anti-Eap antibodies in patients [19]–[21]. Expression is strongly regulated by the two component signalling system SaeRS and to a lesser extent by Agr and SarA [22].…”

Evasion Mechanisms Used by Pathogens to Escape the Lectin Complement Pathway

“…This questions whether the purpose of Eap is to inhibit LP and CP. It has been shown that patients with S. aureus infections have high titers of anti-Eap antibodies confirming the importance of the protein (Joost et al, 2011), but Eap is a multifaceted protein with many functions in S. aureus virulence, which can explain the reported antibody titers (Harraghy et al, 2003). …”