Abstract
The streptococcal collagen-like proteins 1 and 2 (Scl1 and Scl2) are major surface adhesins that are ubiquitous among group A Streptococcus (GAS). Invasive M3-type strains, however, have evolved two unique conserved features in the scl1 locus: (i) an IS1548 element insertion in the scl1 promoter region and (ii) a nonsense mutation within the scl1 coding sequence. The scl1 transcript is drastically reduced in M3-type GAS, contrasting with a high transcription level of scl1 allele in invasive M1-type GAS. This leads to a lack of Scl1 expression in M3 strains. In contrast, while scl2 transcription and Scl2 production are elevated in M3 strains, M1 GAS lack Scl2 surface expression. M3-type strains were shown to have reduced biofilm formation on inanimate surfaces coated with cellular fibronectin and laminin, and in human skin equivalents. Repair of the nonsense mutation and restoration of Scl1 expression on M3-GAS cells, restores biofilm formation on cellular fibronectin and laminin coatings. Inactivation of scl1 in biofilm-capable M28 and M41 strains results in larger skin lesions in a mouse model, indicating that lack of Scl1 adhesin promotes bacterial spread over localized infection. These studies suggest the uniquely evolved scl1 locus in the M3-type strains, which prevents surface expression of the major Scl1 adhesin, contributed to the emergence of the invasive M3-type strains. Furthermore these studies provide insight into the molecular mechanisms mediating colonization, biofilm formation, and pathogenesis of group A streptococci.
Highlights
Group A Streptococcus (GAS) or Streptococcus pyogenes is a human-specific Gram-positive pathogen responsible for significant morbidity and mortality worldwide (Carapetis et al, 2005; Sims Sanyahumbi et al, 2016)
To determine if the IS1548 insertion was specific to M3 strains, we BLAST-searched this element in 45 completed GAS genomes representing 21 different M-types
A complete IS1548 element was not present upstream of scl1.3 in the recently reported genome of the M3 strain STAB902, which represents a non-invasive isolate (Soriano et al, 2014); instead, a 34-bp remnant of IS1548, including the inverted repeat and additional 14 bp, was found. Based on this bioinformatics data, we examined the presence of the IS1548 element upstream of scl1 by PCR in a panel of 40 M3-type strains, using primers located in the IS1548 and scl1.3 sequences (IS1548F and Scl1R, Table S1)
Summary
Group A Streptococcus (GAS) or Streptococcus pyogenes is a human-specific Gram-positive pathogen responsible for significant morbidity and mortality worldwide (Carapetis et al, 2005; Sims Sanyahumbi et al, 2016). Numerous epidemiology studies conducted in the U.S (Stevens et al, 1989; Musser et al, 1991; Cleary et al, 1992; Johnson et al, 1992; DiPersio et al, 1996; Cockerill et al, 1997), Canada (Davies et al, 1996; Kaul et al, 1997; Sharkawy et al, 2002; Hollm-Delgado et al, 2005), and Europe (Gaworzewska and Colman, 1988; Colman et al, 1993; Lamagni et al, 2008; Meisal et al, 2010) have found associations between infections with M1- and M3-type strains and invasive diseases. M3-type strains have been associated with severe invasive disease (Musser et al, 1991; Lamagni et al, 2008) and fatal outcomes (Gaworzewska and Colman, 1988; Colman et al, 1993; Sharkawy et al, 2002)
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