Induction of group A Streptococcus virulence by a human antimicrobial peptide

Abstract

Group A streptococci (Streptococcus pyogenes or GAS) freshly isolated from individuals with streptococcal sore throat or invasive (''flesh-eating'') infection often grow as mucoid colonies on primary culture but lose this colony appearance after laboratory passage. The mucoid phenotype is due to abundant production of the hyaluronic acid capsular polysaccharide, a key virulence determinant associated with severe GAS infections. These observations suggest that signal(s) from the human host trigger increased production of capsule and perhaps other virulence factors during infection. Here we show that subinhibitory concentrations of the human antimicrobial cathelicidin peptide LL-37 stimulate expression of the GAS capsule synthesis operon (hasABC). Up-regulation is mediated by the CsrRS 2-component regulatory system: it requires a functional CsrS sensor protein and can be antagonized by increased extracellular Mg 2؉ , the other identified environmental signal for CsrS. Up-regulation was also evident for other CsrRS-regulated virulence genes, including the IL-8 protease PrtS/ScpC and the integrin-like/IgG protease Mac/IdeS, findings that suggest a coordinated GAS virulence response elicited by this antimicrobial immune effector peptide. LL-37 signaling through CsrRS led to a marked increase in GAS resistance to opsonophagocytic killing by human leukocytes, an in vitro measure of enhanced GAS virulence, consistent with increased expression of the antiphagocytic capsular polysaccharide and Mac/IdeS. We propose that the human cathelicidin LL-37 has the paradoxical effect of stimulating CsrRS-regulated virulence gene expression, thereby enhancing GAS pathogenicity during infection. The ability of GAS to sense and respond to LL-37 may explain, at least in part, the unique susceptibility of the human species to streptococcal infection.

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

“…The expression of various virulence factors produced by S. pyogenes is enhanced by the CovRS two-component system signal transduction pathway under various stress conditions, including the low level of pH, the host antimicrobial peptide LL-37, and a low concentration of extracellular Mg 2ϩ (45)(46)(47)(48)(49). In addition, pepO gene expression has been demonstrated to be negatively regulated by CovRS (17).…”

Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis

“…Akin to this notion, treatment of S. pyogenes with subinhibitory concentrations of the cyclic cationic peptide antibiotic polymyxin B results in localized sites of interaction of the peptide with the bacterium as well as reorganization of SecA from single foci to multiple foci or diffuse localization and a reduction in secretion of some streptococcal toxins (46). Conversely, subinhibitory concentrations of some antimicrobial peptides, such as the cathelicidin LL-37, also can induce the expression of virulence factors in S. pyogenes, suggesting possible opposing responses to CAMPs at sublethal but physiologically plausible levels (47).…”

Severe Acute Otitis Media Caused by Mucoid<i> Streptococcus Pyogenes</i> in a Previously Healthy Adult

“…However, mucoid S. pyogenes has occasionally been reported to cause invasive disease in other countries (Tamayo et al 2010;Wozniak et al 2012). The mucoid phenotype is due to abundant production of the hyaluronic acid capsular polysaccharide, a key virulence factor associated with severe S. pyogenes infection (Gryllos et al 2008). Tamayo et al (2010) described the clinical and molecular characteristics of mucoid strains causing outbreaks of infection, and compared them with non-mucoid S. pyogenes isolated during the same period.…”