Group A streptococci (GAS) are highly prevalent human pathogens whose primary ecological niche is the superficial epithelial layers of the throat and/or skin. Many GAS strains with a strong tendency to cause pharyngitis are distinct from strains that tend to cause impetigo; thus, genetic differences between them may confer host tissue-specific virulence. In this study, the FbaA surface protein gene was found to be present in most skin specialist strains but largely absent from a genetically related subset of pharyngitis isolates. In an ΔfbaA mutant constructed in the impetigo strain Alab49, loss of FbaA resulted in a slight but significant decrease in GAS fitness in a humanized mouse model of impetigo; the ΔfbaA mutant also exhibited decreased survival in whole human blood due to phagocytosis. In assays with highly sensitive outcome measures, Alab49ΔfbaA was compared to other isogenic mutants lacking virulence genes known to be disproportionately associated with classical skin strains. FbaA and PAM (i.e., the M53 protein) had additive effects in promoting GAS survival in whole blood. The pilus adhesin tip protein Cpa promoted Alab49 survival in whole blood and appears to fully account for the antiphagocytic effect attributable to pili. The finding that numerous skin strainassociated virulence factors make slight but significant contributions to virulence underscores the incremental contributions to fitness of individual surface protein genes and the multifactorial nature of GAS-host interactions.KEYWORDS Streptococcus pyogenes, group A streptococci, impetigo, phagocytosis, surface proteins G roup A streptococcus (GAS; Streptococcus pyogenes) is a global human pathogen that causes ϳ750 million infections per year (1, 2). The epithelia of the throat and skin are the primary ecological niches and reservoirs for GAS. It is well established that some GAS strains have a strong predilection for causing infection only at the throat (pharyngitis), whereas other strains have a high tendency to cause superficial infection only at the skin (impetigo). The determinants of tissue site preference for GAS infection and their relative contributions to fitness and virulence are not fully understood.The key sources of structural and functional diversity of GAS exoproteins include the genes within the emm and FCT regions, which map on the chromosome approximately equidistant from the origin of replication, but on opposite sides. Several statistically significant associations between emm region genes (encoding M protein and other surface and secreted proteins), FCT region genes (encoding surface pili and other adhesins), and clinical associations with impetigo versus pharyngitis have been made (reviewed in reference 3). Although there are Ͼ200 emm types, the content and

The secreted cysteine proteinase SpeB is an important virulence factor of group A streptococci (GAS), whereby SpeB activity varies widely among strains. To establish the degree to which SpeB activity correlates with disease, GAS organisms were recovered from patients with pharyngitis, impetigo, invasive disease or acute rheumatic fever (ARF), and selected for analysis using rigorous sampling criteria; >300 GAS isolates were tested for SpeB activity by casein digestion assays, and each GAS isolate was scored as a SpeB-producer or non-producer. Highly significant statistical differences (p < 0.01) in SpeB production are observed between GAS recovered from patients with ARF (41.5% SpeB-non-producers) compared to pharyngitis (20.5%), invasive disease (16.7%), and impetigo (5.5%). SpeB activity differences between pharyngitis and impetigo isolates are also significant, whereas pharyngitis versus invasive isolates show no significant difference. The disproportionately greater number of SpeB-non-producers among ARF-associated isolates may indicate an altered transcriptional program for many rheumatogenic strains and/or a protective role for SpeB in GAS-triggered autoimmunity.