Regulation of capsule gene expression by group A Streptococcus during pharyngeal colonization and invasive infection

Abstract

Capsular polysaccharide production by group A Streptococcus (GAS) is controlled by transcription of the has operon that encodes the enzymes uniquely required for synthesis of the hyaluronic acid polysaccharide. To investigate the regulation of capsule gene expression during infection, we developed a reporter strain of GAS in which the has operon promoter directed transcription of green fluorescent protein (GFP). Gfp expression was triggered within minutes after introduction of the reporter strain into the peritoneal cavity of mice, as evidenced by the recovery of highly fluorescent GAS from the peritoneum 1 h after challenge. Capsule gene expression was also stimulated in the bloodstream of infected mice, as intensely fluorescent bacteria were observed in blood samples collected after either intraperitoneal or intravenous challenge. Using a similar approach, we also observed rapid induction of capsule gene expression in bacteria inoculated into the pharynx of baboons. Compared to the inoculum, increased green fluorescence was recorded in bacteria recovered from throat swabs collected 1 h after inoculation in all five animals studied. We conclude that introduction of GAS into the pharynx or into deep tissues results in rapid induction of has operon expression, a critical adaptive response that enhances GAS survival in the infected host.

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

“…Capsule expression is upregulated in human blood (190,191), and hyperencapsulated (mucoid) strains are frequently isolated from patients with GAS invasive disease (192). Encoded by the highly conserved hasABC synthase operon (193,194), the capsule is a high-molec- ular-mass polymer of glucuronic ␤-1,3-N-acetylglucosamine (195) and is structurally identical to the hyaluronic acid expressed on human cell surfaces and connective tissue, allowing GAS to subvert the host immune response through molecular mimicry (6).…”

A Conserved UDP-Glucose Dehydrogenase Encoded outside the hasABC Operon Contributes to Capsule Biogenesis in Group A Streptococcus

“…GAS capsule expression is strongly upregulated in human blood (29,39), and highly encapsulated, or mucoid, isolates are frequently associated with pharyngeal persistence, acute rheumatic fever, and severe invasive human diseases (32,41). Capsule is also indispensable for the in vivo selection of hypervirulent M1T1 GAS variants harboring mutations within the two-component regulator covRS (11), also known as csrRS (5,35).…”

Modulation ofcovRExpression inStreptococcus mutansUA159

“…The increase in expression at pH 7.2 is not surprising, given that human saliva can be slightly alkaline. Gryllos et al (21,22) reported that the presence of Mg 2ϩ in the growth medium stimulated the activity of CovR/S, specifically acting as a stimulant for CovS. In the absence of CovS, it is possible that Mg 2ϩ activates one of the previously identified TCS of S. mutans (5), which subsequently leads to the transcription of covR or the activation of CovR in S. mutans.…”

“…Expression of covR is also influenced by the nutritional conditions of the extracellular environment; Steiner and Malke (49) reported that amino acid starvation led to the up-regulation of covR transcription by an as-yet-unidentified mechanism. Studies conducted by Gryllos et al (21,22) demonstrated that extracellular Mg 2ϩ was an effective stimulant of CovR/S, leading to the discovery of a subset of genes under the transcriptional control of CovR that had not previously been identified. Chaussee et al (10) reported that Rgg, a transcriptional regulator, positively regulates the expression of the covR/S system.…”