Incremental Contributions of FbaA and Other Impetigo-Associated Surface Proteins to Fitness and Virulence of a Classical Group A Streptococcal Skin Strain

Abstract

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

Thermosensitive pilus production by FCT type 3 Streptococcus pyogenes controlled by Nra regulator translational efficiency

“…Since their discovery, S. pyogenes pili have been shown to promote bacterial adhesion to both human tonsil tissues and human keratinocytes, while they are also known to participate in the biofilm formation and evasion of the host immune system in a serotype‐specific manner (Mora et al , ; Abbot et al , ; Nakata et al , ; Kimura et al , ; Rouchon et al , ; Tsai et al , ). These multiple roles indicate a crucial function of pili during the onset of S. pyogenes infection.…”

Polymorphisms in Regulator of Cov Contribute to the Molecular Pathogenesis of Serotype M28 Group A Streptococcus

“…Consistent with our previously published isogenic DrocA deletion mutant strain transcriptome data, 43 several proven and putative virulence factors had significantly altered transcript levels in the isogenic rocA mutant strains (Supplemental Table S6). Selected virulence factors include the Mga regulon virulence factors 48,49,63 : sclA, 71 fba, 72,73 scpA, 74 enn, 75 emm, 76 mrp, 77 sfbX, 78 and sof (encoding SOF). 79 Other differentially expressed genes are CovRS regulated virulence factors, 29,30 such as nga (encoding SPN), 52 slo (encoding SLO), 52 spyCEP, 80 mac, 81e83 sse, 84 ska (encoding SKA), 85 and speB (encoding SpeB) 54 ( Supplemental Table S6).…”

Molecular Epidemiology, Ecology, and Evolution of Group A Streptococci

“…Whereas 90% of pattern D and E emm types belong to 1 of the 16 emm clusters, nearly half of pattern A-C emm types are standalone and do not cluster with any other emm type, highlighting once again a distinct dynamic for the evolution of many pattern A-C emm types. Another possible factor at play in shaping the evolution of emm type-specific sequences is functional constraints, such as those imposed by binding C4BP via the type-specific region of numerous M proteins (166)(167)(168). Whole GAS organisms that bind C4BP tend to harbor M types associated with emm pattern groups D and E (167).…”