Analysis of the Streptococcal Hemoprotein Receptor: A Role in Virulence and Host Defense

Group A streptococcus (GAS) is an important pathogen that produces a wide spectrum of suppurative infections and autoimmune sequelae in humans, ranging from less complex pharyngitis, impedigo to more severe manifestations such as necrotizing fasciitis, toxic shock syndrome, rheumatic fever and glomerulonephritis. The worldwide burden of GAS infections and sequelae is considerable, but an immunization program that defends against the hypervariable GAS is missing. The streptococcal hemoprotein receptor (Shr), is an iron-regulated protein involved in heme acquisition. An unspecified region in the amino terminus of Shr mediates the interactions with hemoglobin and two protein modules named NEAT1 and NEAT2 bind heme. In this study, we analyzed the molecular structure and function of Shr, investigated its antigenic properties and role in GAS disease production. We demonstrated that Shr is a new type of GAS adhesin that contributes to the pathogen interactions with extracellular matrix (ECM) proteins. Shr enabled bacterial adherence to host cells and was important for GAS virulence in vivo. Immunizations with Shr protein by intraperitoneal or intranasal administration conferred resistance to systemic GAS challenge in mice. Shr antiserum allowed bacterial opsonization and defended against GAS diseases in a murine model for passive vaccination. Studies with isolated Shr domains localized ECM-binding to the NEAT domains and showed that most of the protein is exposed on the bacterial surface. In addition, Shr N-terminal region and both of the NEAT modules elicited strong antibody response in rabbits. In conclusion, Shr is a protective antigen that contributes to GAS pathogenesis by facilitating both heme uptake and bacterial adherence. Since Shr is conserved among GAS strains and other pyogenic streptococci, this study demonstrates that Shr may be used to develop a vaccine against GAS strains and related pathogens. INDEX WORDS: Streptococcus pyogenes, Sia operon, Adherence, Adhesin, Fibronectin, MSCRAMM, NEAT domain, Virulence, Immunization, Vaccine ANALYSIS OF THE STREPTOCOCCAL HEMOPROTEIN RECEPTOR: A ROLE IN VIRULENCE AND HOST DEFENSE