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Identifying genetic variations in emm89 Streptococcus pyogenes associated with severe invasive infections
Masayuki Ono1,2, Masaya Yamaguchi1,2,3,4,5, Daisuke Motooka3,6,7
1Department of Microbiology, Graduate School of Dentistry, The University of Osaka, Osaka, Japan.
Abstract:
Streptococcus pyogenes causes mild human infections as well as life-threatening invasive diseases. Since the mutations known to enhance virulence to date account for only half of the severe invasive infections, additional mechanisms/mutations need to be identified. Here, we conducted a genome-wide association study of emm89 S. pyogenes strains to comprehensively identify pathology-related bacterial genetic factors (single-nucleotide polymorphisms [SNPs], indels, genes, or k-mers). Japanese (n = 311) and global (n = 666) cohort studies of strains isolated from invasive or non-invasive infections revealed 17 and 1075 SNPs/indels and 2 and 169 genes, respectively, that displayed associations with invasiveness. We validated one of them, a non-invasiveness-related point mutation, fhuB T218C, by structure predictions and introducing it into a severe invasive strain and confirmed that the mutant showed slower growth in human blood. Thus, we report novel mechanisms that convert emm89 S. pyogenes to an invasive phenotype and a platform for establishing novel treatments and prevention strategies.
Insights
New genetic factors in Streptococcus pyogenes (emm89) were identified that contribute to invasive disease. This research uncovers novel mechanisms driving severe infections, paving the way for new treatments.
Area of Science:
- Microbiology
- Genetics
- Infectious Diseases
Background:
- Streptococcus pyogenes causes a spectrum of infections, from mild to life-threatening invasive diseases.
- Current knowledge on virulence-enhancing mutations explains only half of severe invasive infections, necessitating further research.
Purpose of the Study:
- To comprehensively identify bacterial genetic factors (SNPs, indels, genes, k-mers) associated with the invasiveness of emm89 Streptococcus pyogenes strains.
- To discover novel mechanisms contributing to the invasive potential of Streptococcus pyogenes.
Main Methods:
- Genome-wide association study (GWAS) on Japanese (n=311) and global (n=666) emm89 Streptococcus pyogenes strains.
- Analysis of strains from invasive and non-invasive infections to identify genetic associations with invasiveness.
- Validation of identified genetic factors, including the fhuB T218C mutation, through structural predictions and experimental manipulation.
Main Results:
- GWAS identified 17 SNPs/indels and 2 genes associated with invasiveness in Japanese strains.
- A larger global cohort revealed 1075 SNPs/indels and 169 genes associated with invasiveness.
- The fhuB T218C mutation was validated as a non-invasiveness factor, with the mutant strain exhibiting slower growth in human blood.
Conclusions:
- Novel genetic factors and mechanisms that contribute to the invasive phenotype of emm89 Streptococcus pyogenes have been identified.
- This study provides a foundation for developing new therapeutic and preventative strategies against invasive Streptococcus pyogenes infections.
- The identified genetic factors offer potential targets for interventions aimed at reducing the severity of Streptococcus pyogenes diseases.
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