Date Published: January 25, 2017
Publisher: Public Library of Science
Author(s): Amonrattana Roobthaisong, Chihiro Aikawa, Takashi Nozawa, Fumito Maruyama, Ichiro Nakagawa, Sean Reid.
Streptococcus pyogenes (group A Streptococcus, or GAS) is a human pathogen that causes a wide range of diseases. For successful colonization within a variety of host niches, GAS utilizes TCSs to sense and respond to environmental changes and adapts its pathogenic traits accordingly; however, many GAS TCSs and their interactions remain uncharacterized. Here, we elucidated the roles of a poorly characterized TCS, YvqEC, and a well-studied TCS, CovRS, in 2 different GAS strain SSI-1 and JRS4, respectively. Deletion of yvqE and yvqC in JRS4 resulted in lower cell viability and abnormality of cell division when compared to the wild-type strain under standard culture conditions, demonstrating an important role for YvqEC. Furthermore, a double-deletion of yvqEC and covRS in SSI-1 and JRS4 resulted in a significantly impaired ability to survive under various stress conditions, as well as an increased sensitivity to cell wall-targeting antibiotics compared to that observed in either single mutant or wild-type strains suggesting synergistic interactions. Our findings provide new insights into the impact of poorly characterized TCS (YvqEC) and potential synergistic interactions between YvqEC and CovRS and reveal their potential role as novel therapeutic targets against GAS infection.
Streptococcus pyogenes (group A Streptococcus; GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from mild infections of the upper respiratory tract (pharyngitis) and skin (impetigo) to more serious invasive infections such as necrotizing fasciitis and streptococcal toxic shock syndrome (STSS) . To successfully colonize and persist in a number of physiologically distinct host sites, GAS has developed complex mechanisms to cope with various environmental stresses. In many other gram-positive bacteria, sigma factors have been shown to play an essential role in the regulation of virulence genes in response to stress or growth . However, GAS does not encode alternative sigma factors for regulating virulence gene expression . Two-component systems (TCSs) are typically composed of two proteins, a sensor histidine kinase (HK) and its cognate response regulator (RR). TCSs are typically involved in various physiological functions in bacteria, such as survival, motility, metabolism, antibiotic resistance, stress response, and virulence, by sensing changes in the external or internal environment, modulating gene expression in response to a variety of stimuli inside the host cells, and avoiding host immune systems .
Bacterial cell wall synthesis is crucial for bacterial cell growth, division, and structure, and penicillin-binding proteins (PBPs) are involved in bacterial cell wall formation. Inhibition of PBPs leads to irregularities in cell wall structure and eventual cell death. The ftsL gene is required for the initiation of cell division in a broad range of bacteria. Therefore, FtsL appears to be essential in S. pneumoniae, E. coli, and B. subtilis [36–38]. Cell viability and division in JRS4ΔyvqE and JRS4ΔyvqC cells were defective, and downregulation of pbp1B and ftsL expression was observed (S3 Table), suggesting that the YvqEC system may play a role in regulating cell wall synthesis and division under normal growth conditions. It is unclear how yvqE and yvqC affect cell viability and division under standard culture conditions, and future studies will assess in more detail, as previous reports [9–18] do not indicate that YvqEC, or its homologs, are important for cell viability and division in GAS or other gram-positive bacteria. VicRK system, which is also known as YycFG or WalRK, is highly conserved and is essential for the viability of GAS [39, 40] and other gram-positive bacteria such as B. subtilis , S. aureus , S. pneumoniae , and S. mutans . It is possible that YvqEC system in JRS4 serves as a regulatory network, with VicRK being responsible for the control of cell viability.