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Hypervariability generated by natural selection in an extracellular complement-inhibiting protein of serotype M1
K E Stockbauer1, D Grigsby, X Pan
1Institute for the Study of Human Bacterial Pathogenesis, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Abstract:
In many countries, M1 strains of the human pathogenic bacterium group A Streptococcus are the most common serotype recovered from patients with invasive disease episodes. Strains of this serotype express an extracellular protein that inhibits complement [streptococcal inhibitor of complement (Sic)] and is therefore believed to be a virulence factor. Comparative sequence analysis of the 915-bp sic gene in 165 M1 organisms recovered from diverse localities and infection types identified 62 alleles. Inasmuch as multilocus enzyme electrophoresis and pulsed-field gel electrophoresis previously showed that most M1 organisms represent a distinct streptococcal clone, the extent of sic gene polymorphism was unexpected. The level of polymorphism greatly exceeds that recorded for all other genes examined in serotype M1 strains. All insertions and deletions are in frame, and virtually all nucleotide substitutions alter the amino acid sequence of the Sic protein. These molecular features indicate that structural change in Sic is mediated by natural selection. Study of 70 strains recovered from two temporally distinct epidemics of streptococcal infections in the former East Germany found little sharing of Sic variants among strains recovered in the different time periods. Taken together, the data indicate that sic is a uniquely variable gene and provide insight into a potential molecular mechanism contributing to fluctuations in streptococcal disease frequency and severity.
Insights
Group A Streptococcus M1 strains possess a highly variable virulence factor, the streptococcal inhibitor of complement (Sic) protein. This genetic diversity suggests natural selection and may explain changes in disease severity and frequency.
Area of Science:
- Microbiology
- Bacterial Pathogenesis
- Molecular Evolution
Background:
- M1 strains of group A Streptococcus are prevalent in invasive infections.
- The extracellular protein, streptococcal inhibitor of complement (Sic), is a key virulence factor.
- The sic gene's polymorphism was unexpectedly high given the clonal nature of M1 strains.
Purpose of the Study:
- To investigate the genetic diversity of the sic gene in M1 group A Streptococcus.
- To understand the evolutionary mechanisms driving sic gene variation.
- To explore the link between sic gene polymorphism and disease epidemiology.
Main Methods:
- Comparative sequence analysis of the sic gene from 165 M1 strains.
- Analysis of strains from temporally distinct epidemics in East Germany.
- Assessment of nucleotide substitutions, insertions, and deletions within the sic gene.
Main Results:
- Identified 62 distinct alleles of the sic gene among 165 M1 strains.
- Observed significantly higher polymorphism in the sic gene compared to other M1 strain genes.
- Found limited sharing of Sic variants between strains from different epidemic periods.
- Demonstrated that most nucleotide substitutions result in amino acid changes, indicating functional impact.
Conclusions:
- The sic gene exhibits unique and extensive variability in M1 group A Streptococcus.
- Natural selection actively drives structural changes in the Sic protein.
- Sic gene polymorphism may contribute to the fluctuating frequency and severity of streptococcal diseases.