Premium
Polymorphisms in RocA contribute to the molecular pathogenesis of serotype M28 group A streptococcus
Author(s) -
Bernard Paul Edward,
Kachroo Priyanka,
Eraso Jesus M.,
Zhu Luchang,
Madry Jessica E.,
Duarte Amey,
Linson Sarah E.,
Saavedra Matthew Ojeda,
Cantu Concepcion,
Musser James M.,
Olsen Randall J.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03097
Subject(s) - virulence , biology , transcriptome , genetics , phenotype , genome , gene , gene expression
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), RocA (regulator of Cov) is an accessory protein that functions with the CovRS (control of virulence regulator/sensor) TCS. Previous data suggest that the N‐terminal predicted transmembrane domains are important for RocA function and interaction with the CovRS TCS. 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, an isogenic rocA deletion mutant strain, and isogenic rocA polymorphism mutant strains to perform genome‐wide transcript analysis (RNA‐seq), 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. Additionally, in contrast to previously published data on functional domains of RocA, polymorphisms in both the N‐terminal transmembrane domains and the C‐terminal predicted non‐functional histidine kinase ATPase domain result in an altered virulence phenotype suggestive of loss of RocA activity. 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. Support or Funding Information Fondren Foundation, Houston Methodist Hospital and Research Institute (to JMM and PEB)American Heart Association Predoctoral Fellowship award 19PRE34380820 (to PEB)NIH grants R21AI139369‐01A1 and R21AI146771‐01 (to JMM)