Abstract
Transcriptional regulatory networks are fundamental to how microbes alter gene expression in response to environmental stimuli, thereby playing a critical role in bacterial pathogenesis. However, understanding how bacterial transcriptional regulatory networks function during host-pathogen interaction is limited. Recent studies in group A Streptococcus (GAS) suggested that the transcriptional regulator catabolite control protein A (CcpA) influences many of the same genes as the control of virulence (CovRS) two-component gene regulatory system. To provide new information about the CcpA and CovRS networks, we compared the CcpA and CovR transcriptomes in a serotype M1 GAS strain. The transcript levels of several of the same genes encoding virulence factors and proteins involved in basic metabolic processes were affected in both ΔccpA and ΔcovR isogenic mutant strains. Recombinant CcpA and CovR bound with high-affinity to the promoter regions of several co-regulated genes, including those encoding proteins involved in carbohydrate and amino acid metabolism. Compared to the wild-type parental strain, ΔccpA and ΔcovRΔccpA isogenic mutant strains were significantly less virulent in a mouse myositis model. Inactivation of CcpA and CovR alone and in combination led to significant alterations in the transcript levels of several key GAS virulence factor encoding genes during infection. Importantly, the transcript level alterations in the ΔccpA and ΔcovRΔccpA isogenic mutant strains observed during infection were distinct from those occurring during growth in laboratory medium. These data provide new knowledge regarding the molecular mechanisms by which pathogenic bacteria respond to environmental signals to regulate virulence factor production and basic metabolic processes during infection.
Highlights
It has long been recognized that the gene expression profile of bacterial pathogens differs significantly during infection compared to the laboratory environment [1]
We discovered that two Group A Streptococcus (GAS) proteins, catabolite control protein A (CcpA) and control of virulence regulator (CovR), regulate production of many of the same virulence factor encoding genes, indicating that GAS uses these two regulatory proteins to modulate virulence factor production in response to environmental stimuli
Using a mouse model of muscle infection, we found that CcpA and CovR, alone and in combination, are critical to the ability of GAS to regulate expression of virulence factor encoding genes during infection
Summary
It has long been recognized that the gene expression profile of bacterial pathogens differs significantly during infection compared to the laboratory environment [1]. There is a dearth of information available regarding how transcriptional regulatory networks function in response to host environmental stimuli to determine virulence factor production [5]. The ability of GAS to cause infection in diverse human niches indicates that GAS has evolved precise mechanisms to alter gene expression depending on the distinct challenges posed by particular disease sites [7,8,9]. Gene expression in GAS is heavily dependent on transcriptional regulatory networks [12]. Interaction between TCS and standalone regulators is clearly critical to bacterial pathogenesis, information regarding how independent bacterial regulators coordinate gene expression during infection is lacking
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
