Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis

Abstract

The sequences reported in this paper have been deposited in the National Center for Biotechnology Information (NCBI) Sequence Read Archive (see URLs) with the Bioproject accession number PRJNA434389 and the NCBI Gene Expression Omnibus (GEO) under accession number GSE113058. ETHICS STATEMENTAll mouse studies were performed in accordance with a protocol (AUP-0318-0016) approved by the Institutional Animal Care and Use Committee at Houston Methodist Research Institute. All studies with human blood and blood components were performed in accordance with a protocol (01-I-N055) approved by the Institutional Review Board for human subjects, National Institute of Allergy and Infectious Diseases. All study volunteers gave written informed consent.

Genetic heterogeneity of the Spy1336/R28 – Spy1337 Virulence Axis inStreptococcus pyogenesand Effect on Gene Transcript Levels and Pathogenesis

“…We previously discovered that a single nucleotide indel located in an HT in the intergenic region between the divergently transcribed Spy1336/R28 and Spy1337 genes ( Fig. 1A and B) significantly altered the transcript levels of the two genes (38). Specifically, strains with 9Ts in the HT produced little or no detectable transcript of these two genes, whereas organisms with 10Ts in this tract produced abundant and significantly increased levels of transcripts (38).…”

“…1A and B) significantly altered the transcript levels of the two genes (38). Specifically, strains with 9Ts in the HT produced little or no detectable transcript of these two genes, whereas organisms with 10Ts in this tract produced abundant and significantly increased levels of transcripts (38). Moreover, increased transcript levels of Spy1336/R28…”

“…Recently, we proposed that the Spy1337 protein is a positive transcriptional regulator of both Spy1336/R28 and Spy1337, and that by regulating expression of Spy1336/R28 and other genes, Spy1337 is involved in emm28 GAS virulence (38). To positively regulate virulence gene expression, AraC-like transcriptional regulators usually either bind to chemical effectors present at the site of infection to cause a conformational change favoring DNAbinding to their cognate gene targets (39,40), or they bind to AraC negative regulators (ANRs) that inhibits such interactions (41).…”

“…In addition, compared to the isogenic strain with 9Ts, the strain with 10Ts was significantly more resistant to killing by human polymorphonuclear leukocytes ex vivo and produced more R28 protein. Thus, a one-nucleotide indel in the HT Spy1336-7 caused altered level of these two transcripts and changed the virulence phenotype (38). Of note, there is an HT comprised of 8-15 T residues located in the regulatory region 99 nucleotides (nts) upstream of the bca gene encoding the GBS alpha C Alp protein (64).…”

“…invasive clinical isolates, including the reference strain MGAS6180, for which we had whole genome and transcriptome data (38). Finally, we used isogenic mutant strains to determine the contributions of Spy1336/R28 and Spy1337 to global gene expression and virulence.…”