Heme Acquisition in Group A Streptococcus

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DESCRIPTION (provided by applicant): Hemolytic Streptococcus pyogenes, commonly referred as Group A Streptococcus (GAS), is an important human pathogen causing pharyngitis, cellulitis, scarlet fever, necrotizing fasciitis, toxic shock syndrome, acute rheumatic fever, rheumatic heart disease, and glomerulonephritis. The pathogenesis of GAS infection is mediated by an abundance of virulence factors which make effective immunotherapeutic control of GAS diseases extremely difficult. Iron acquisition systems of many bacterial pathogens are key virulence factors. Their role in virulence, conserved antigenicity, and surface exposure make them attractive vaccine candidates. GAS can sequester iron from hemoglobin and heme is thought to be the primary iron source for GAS in vivo. However, little is known about the machinery for heme acquisition in GAS. Recently, we identified a novel heme-associated cell-surface protein (designated Shp1) made by GAS. The shp 1 gene is co-transcribed with 8 contiguous downstream genes, including spy1795, spy1794, and spy1793 encoding homologues of the components of ABC transporters involved in iron uptake in Gramnegative bacteria. My preliminary results suggest that the lipoprotein component (Spy1795, designated Shp2) of the GAS putative transporter also binds heme. The proposed studies will investigate whether the sht locus (containing shp1 and shp2) encodes the machinery for heme acquisition in GAS and if sht is required for GAS virulence. I plan to achieve the following specific aims using biochemical and genetic approaches and infection models to define the role of heme acquisition in GAS pathogenesis. Aim 1. Determine whether recombinant Shp2 binds heme Aim 2. Elucidate if the sht locus encodes a transporter system for heme acquisition Aim 3. Investigate whether the disruption of shp1 and/or shp2 attenuates GAS virulence The study will advance our understanding of the mechanism of heme acquisition in GAS and may identify new potential GAS vaccine candidate(s).