B-170. Induction of Group A Streptococcus Virulence by a Human Antimicrobial Peptide

I. Gryllos1,2, M-F. Cheng3, H. Chung2, R. Bolcome III2, W. Lu4, R. I. Lehrer5, M. R. Wessels1,2;
1Children's Hosp., Boston, MA, 2Harvard Med. Sch., Boston, MA, 3Veterans Gen. Hosp.-Kaohsiung, Natl. Yang-Ming Univ., Taipei, TAIWAN, 4Inst. of Human Virology, Univ. of Maryland, Baltimore, MD, 5David Geffen Sch. of Med., Univ. of California, Los Angeles, CA.

Group A Streptococcus (S. pyogenes or GAS) freshly isolated from individuals with streptococcal pharyngitis or invasive infection often appears more virulent than the same strain after culture in vitro. However, neither the host factor that triggers up-regulation of GAS pathogenicity during human infection nor the bacterial system that transduces the host signal is known. In this study we have used a capsule gene expression reporter strain and quantitative RT-PCR to show that subinhibitory concentrations of the human antimicrobial cathelicidin peptide LL-37 signal through the GAS CsrRS (CovRS) two-component regulatory system to increase bacterial virulence. LL-37, but not other human antimicrobial peptides, stimulated increased production of CsrRS-regulated virulence factors in independent GAS isolates including the hyaluronic acid capsular polysaccharide, the IL-8 protease PrtS/ScpC, and the antiphagocytic factor/IgG protease Mac-1/IdeS. Regulation was dependent on a functional CsrS sensor protein, as indicated by the lack of response in a csrS mutant, and could be antagonized by increased extracellular Mg2+, the other identified signal for CsrRS. CsrRS signaling by LL-37 markedly enhanced the capacity of GAS to proliferate in fresh human blood, an in vitro measure of GAS resistance to host innate defenses and phagocytosis and a correlate of GAS virulence. Thus, LL-37 stimulation of CsrRS-regulated virulence gene expression enhances GAS pathogenicity and may explain, at least in part, the unique susceptibility of the human species to GAS infection.