Staphylococcus aureus Manganese Transport Protein C Is a Highly Conserved Cell Surface Protein That Elicits Protective Immunity Against S. aureus and Staphylococcus epidermidis

Staphylococci cause diseases ranging from relatively mild superficial skin infections to life-threatening conditions, including sepsis and endocarditis. Increasingly, staphylococci have developed antibiotic resistance, reducing treatment options and highlighting the need for an effective prophylactic vaccine. Preclinical studies have assessed several antigens that, either alone [1, 2] or in combination [3], have the ability to reduce staphylococcal disease in preclinical models. Staphylococcal strains are known for the phenotypic plasticity of their antigenic repertoire, which provides mechanisms for both survival in diverse host niches and for immune evasion. Thus the development of a broadly protective vaccine that can prevent different diseases caused by diverse strains from within the species group poses challenges. S. aureus distinguishes itself from other staphylococci by an impressive array of virulence factors [4] and the production of coagulase. S. epidermidis also causes disease with associated mortality [5, 6]. S. aureus and S. epidermidis share a core genome representing approximatly two thirds of their genes; the proteins encoded by the core genesaverage 70% amino acid sequence identity between the two organisms [4]. We were interested in evaluating proteins with the potential to prevent staphylococcal disease caused by either S. aureus or S. epidermidis. Effective bacterial vaccine components should be conserved and perform important functions during infection. Initial attempts to identify S. aureus vaccine candidates came from assessment of surface antigens from bacteria grown in vitro [7]. Advances in in vivo technology have led to a better understanding of bacterial antigen expression during infection, enhancing our knowledge of host-pathogen relationships. When S. aureus and other pathogenic bacteria invade, they initiate expression of multiple virulence pathways. S. aureus produces capsular polysaccharide to avoid attack from the innate immune system. It also expresses various ligand-binding proteins with roles ranging from immune cloaking [8] to scavenging essential ions [9]. One group of proteins associated with in vivo survival of S. aureus are the manganese transport (Mnt) proteins. The Mnt complex is an ABC transporter composed of an ATP-binding protein (MntA), an integral membrane transporter (MntB), and a manganese binding surface lipoprotein (MntC) [10]. Recently MntC was identified as being expressed on the cell surface of S. aureus in biofilms generated in in vivo models of infection [11]. The orthologous protein in S. epidermidis is staphylococcal iron transport C (SitC) [12], which was detected in convalescent-phase serum from rabbits infected with S. epidermidis and found to be protective in a S. epidermidis murine kidney abscess model [13]. A critical attribute for an effective staphylococcal vaccine antigen is early expression during infection, which provides an opportunity for vaccine-induced antibodies to inactivate bacteria before infection is firmly established. We therefore evaluated S. aureus MntC temporal expression in vivo. S. aureus MntC and S. epidermidis SitC have a high level of sequence identity (72%), and polyclonal antisera have been demonstrated to be cross-reactive [13]. We explored whether S. aureus MntC could produce cross-protective antibodies against both S. aureus and S. epidermidis infection.