Survey of the bp/tee genes from clinical group A streptococcus isolates in New Zealand – implications for vaccine development

Abstract

Group A streptococcus (GAS) is responsible for a wide range of diseases ranging from superficial infections, such as pharyngitis and impetigo, to life-threatening diseases, such as toxic shock syndrome and acute rheumatic fever (ARF). GAS pili are hair-like extensions protruding from the cell surface and consist of highly immunogenic structural proteins: the backbone pilin (BP) and one or two accessory pilins (AP1 and AP2). The protease-resistant BP builds the pilus shaft and has been recognized as the T-antigen, which forms the basis of a major serological typing scheme that is often used as a supplement to M typing. A previous sequence analysis of the bp gene (tee gene) in 39 GAS isolates revealed 15 different bp/tee types. In this study, we sequenced the bp/tee gene from 100 GAS isolates obtained from patients with pharyngitis, ARF or invasive disease in New Zealand. We found 20 new bp/tee alleles and four new bp/tee types/ subtypes. No association between bp/tee type and clinical outcome was observed. We confirmed earlier reports that the emm type and tee type are associated strongly, but we also found exceptions, where multiple tee types could be found in certain M/emm type strains, such as M/ emm89. We also reported, for the first time, the existence of a chimeric bp/tee allele, which was assigned into a new subclade (bp/tee3.1). A strong sequence conservation of the bp/tee gene was observed within the individual bp/tee types/subtypes (.97 % sequence identity), as well as between historical and contemporary New Zealand and international GAS strains. This temporal and geographical sequence stability provided further evidence for the potential use of the BP/Tantigen as a vaccine target.

Group A Streptococcus T Antigens Have a Highly Conserved Structure Concealed under a Heterogeneous Surface That Has Implications for Vaccine Design

“…As evidence, a recent whole-genome sequencing (WGS) study of over 1,400 invasive GAS isolates in the United States clustered GAS into 21 different tee types (15). Unfortunately, the annotation of tee types in this WGS study differed from those reported previously (13,14), which highlights a need to harmonize tee typing nomenclature to avoid future confusion.…”

“…GAS pilin genes, together with genes encoding pilus assembly sortases, are found in a single operon within the FCT (fibronectin-binding, collagen-binding, T antigen) region (9,11,12). Overall, the tee gene shows less genetic variability than the emm gene: previous surveys of the tee gene in GAS strains have identified 18 major tee types, 3 of which can be further split into subtypes (13,14). These studies, although of a relatively small scale (39 and 100 GAS strains, respectively), appear to have captured the vast majority of tee type diversity.…”

“…Indeed, our previous phylogenetic study predicted that 16 of the 21 tee types and subtypes encode T antigens comprised of two domains (14). Furthermore, GAS strains expressing the two-domain T antigens are the most diverse in terms of the number of associated emm types and are associated with significant disease (9,14). Unlike T6, the T1 antigen structure lacks large hypervariant extensions.…”

The Group A Streptococcus serotype M2 pilus plays a role in host cell adhesion and immune evasion

“…The components of GAS pili have long been considered as potential vaccine candidates due to their important roles in pathogenesis and high immunogenicity (Soriani and Telford, 2010;Moreland et al, 2014). A number of surveys have been done to evaluate the coverage of pilus-based GAS vaccines (Falugi et al, 2008;Steemson et al, 2014). Therefore, studies investigating the less-studied pili such as the FCT-6 pilus presented in this work will provide better understanding for this highly dynamic structure.…”

Tissue tropisms in group A Streptococcus

“…Sequence heterogeneity is particularly high among pilin backbone proteins (e.g., FctA), pilin tip proteins (e.g., Cpa) and the N-terminal half of PrtF1/SfbI [44,45,60]. Some structural forms of Cpa have two distinct TEDs, whereas other Cpa forms are devoid of putative TEDs [56,57▪].…”