Polymorphisms in Regulator of Cov Contribute to the Molecular Pathogenesis of Serotype M28 Group A Streptococcus

Research output: Contribution to journalArticle

Authors

  • Paul E. Bernard
  • Priyanka Kachroo
  • Jesus M. Eraso
  • Luchang Zhu
  • Jessica E. Madry
  • Sarah E. Linson
  • Matthew Ojeda Saavedra
  • Concepcion Cantu
  • James M. Musser
  • Randall J. Olsen

External Institution(s)

  • Houston Methodist Hospital
  • Cornell University
  • Texas A&M University

Details

Original languageEnglish (US)
Pages (from-to)2002-2018
Number of pages17
JournalAmerican Journal of Pathology
Volume189
Issue number10
StatusPublished - Oct 2019
Peer-reviewedYes

Abstract

Two-component systems (TCSs) are signal transduction proteins that enable bacteria to respond to external stimuli by altering the global transcriptome. Accessory proteins interact with TCSs to fine-tune their activity. In group A Streptococcus (GAS), regulator of Cov (RocA) is an accessory protein that functions with the control of virulence regulator/sensor TCS, which regulates approximately 15% of the GAS transcriptome. Whole-genome sequencing analysis of serotype M28 GAS strains collected from invasive infections in humans identified a higher number of missense (amino acid–altering) and nonsense (protein-truncating) polymorphisms in rocA than expected. We hypothesized that polymorphisms in RocA alter the global transcriptome and virulence of serotype M28 GAS. We used naturally occurring clinical isolates with rocA polymorphisms (n = 48), an isogenic rocA deletion mutant strain, and five isogenic rocA polymorphism mutant strains to perform genome-wide transcript analysis (RNA sequencing), in vitro virulence factor assays, and mouse and nonhuman primate pathogenesis studies to test this hypothesis. Results demonstrated that polymorphisms in rocA result in either a subtle transcriptome change, causing a wild-type–like virulence phenotype, or a substantial transcriptome change, leading to a significantly increased virulence phenotype. Each polymorphism had a unique effect on the global GAS transcriptome. Taken together, our data show that naturally occurring polymorphisms in one gene encoding an accessory protein can significantly alter the global transcriptome and virulence phenotype of GAS, an important human pathogen.

Citation formats

APA

Bernard, P. E., Kachroo, P., Eraso, J. M., Zhu, L., Madry, J. E., Linson, S. E., ... Olsen, R. J. (2019). Polymorphisms in Regulator of Cov Contribute to the Molecular Pathogenesis of Serotype M28 Group A Streptococcus. American Journal of Pathology, 189(10), 2002-2018. https://doi.org/10.1016/j.ajpath.2019.06.009

Harvard

Bernard, PE, Kachroo, P, Eraso, JM, Zhu, L, Madry, JE, Linson, SE, Ojeda Saavedra, M, Cantu, C, Musser, JM & Olsen, RJ 2019, 'Polymorphisms in Regulator of Cov Contribute to the Molecular Pathogenesis of Serotype M28 Group A Streptococcus', American Journal of Pathology, vol. 189, no. 10, pp. 2002-2018. https://doi.org/10.1016/j.ajpath.2019.06.009