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Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with
James C Smoot1, Kent D Barbian, Jamie J Van Gompel
1Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840, USA.
Abstract:
Acute rheumatic fever (ARF), a sequelae of group A Streptococcus (GAS) infection, is the most common cause of preventable childhood heart disease worldwide. The molecular basis of ARF and the subsequent rheumatic heart disease are poorly understood. Serotype M18 GAS strains have been associated for decades with ARF outbreaks in the U.S. As a first step toward gaining new insight into ARF pathogenesis, we sequenced the genome of strain MGAS8232, a serotype M18 organism isolated from a patient with ARF. The genome is a circular chromosome of 1,895,017 bp, and it shares 1.7 Mb of closely related genetic material with strain SF370 (a sequenced serotype M1 strain). Strain MGAS8232 has 178 ORFs absent in SF370. Phages, phage-like elements, and insertion sequences are the major sources of variation between the genomes. The genomes of strain MGAS8232 and SF370 encode many of the same proven or putative virulence factors. Importantly, strain MGAS8232 has genes encoding many additional secreted proteins involved in human-GAS interactions, including streptococcal pyrogenic exotoxin A (scarlet fever toxin) and two uncharacterized pyrogenic exotoxin homologues, all phage-associated. DNA microarray analysis of 36 serotype M18 strains from diverse localities showed that most regions of variation were phages or phage-like elements. Two epidemics of ARF occurring 12 years apart in Salt Lake City, UT, were caused by serotype M18 strains that were genetically identical, or nearly so. Our analysis provides a critical foundation for accelerated research into ARF pathogenesis and a molecular framework to study the plasticity of GAS genomes.
Insights
Sequencing the genome of a Group A Streptococcus (GAS) M18 strain provides insights into acute rheumatic fever (ARF) pathogenesis. This study reveals genetic variations, including phage-associated toxins, crucial for understanding ARF development.
Area of Science:
- Microbiology
- Genomics
- Immunology
Background:
- Acute rheumatic fever (ARF) is a significant cause of childhood heart disease globally, stemming from Group A Streptococcus (GAS) infections.
- The precise molecular mechanisms underlying ARF and rheumatic heart disease remain largely unknown.
- Serotype M18 GAS strains are frequently implicated in ARF outbreaks in the United States.
Purpose of the Study:
- To investigate the genomic basis of ARF pathogenesis by sequencing the M18 GAS strain MGAS8232.
- To identify genetic differences and potential virulence factors contributing to ARF.
- To establish a molecular framework for studying GAS genome plasticity and ARF development.
Main Methods:
- Whole-genome sequencing of the M18 GAS strain MGAS8232.
- Comparative genomic analysis with a previously sequenced M1 GAS strain (SF370).
- DNA microarray analysis of 36 diverse M18 GAS strains.
Main Results:
- The MGAS8232 genome is a 1.89 Mb circular chromosome.
- Significant genetic variation exists between M18 and M1 GAS strains, primarily due to phages and mobile genetic elements.
- MGAS8232 possesses unique genes encoding secreted proteins, including streptococcal pyrogenic exotoxin A and other phage-associated toxins, potentially influencing host-pathogen interactions.
- M18 strains from geographically diverse locations and distinct ARF outbreaks showed remarkable genetic similarity, particularly concerning phage content.
Conclusions:
- The genomic data provides a foundational understanding of ARF pathogenesis.
- Phage-associated genes and secreted toxins represent key areas for future research into ARF virulence.
- GAS genomes exhibit significant plasticity, driven by mobile genetic elements, which may impact disease epidemiology.