Streptococcal Inhibitor of Complement Inhibits Two Additional Components of the Mucosal Innate Immune System: Secretory Leukocyte Proteinase Inhibitor and Lysozyme

Abstract

Streptococcal inhibitor of complement (SIC) is a 31-kDa extracellular protein of a few, very virulent, strains of Streptococcus pyogenes (particularly M1 strains). It is secreted in large quantities (about 5 mg/liter) and inhibits complement lysis by blocking the membrane insertion site on C5b67. We describe investigations into the interaction of SIC with three further major components of the innate immune system found in airway surface liquid, namely, secretory leukocyte proteinase inhibitor (SLPI), lysozyme, and lactoferrin. Enzymelinked immunosorbent assays showed that SIC binds to SLPI and to both human and hen egg lysozyme (HEL) but not to lactoferrin. Studies using 125 I-labeled proteins showed that SIC binds approximately two molecules of SLPI and four molecules of lysozyme. SLPI binding shows little temperature dependence and a small positive enthalpy, suggesting that the binding is largely hydrophobic. By contrast, lysozyme binding shows strong temperature dependence and a substantial negative enthalpy, suggesting that the binding is largely ionic. Lysozyme is precipitated from solution by SIC. Further studies examined the ability of SIC to block the biological activities of SLPI and lysozyme. An M1 strain of group A streptococci was killed by SLPI, and the antibacterial activity of this protein was inhibited by SIC. SIC did not inhibit the antiproteinase activity of SLPI, implying that there is specific inhibition of the antibacterial domain. The antibacterial and enzymatic activities of lysozyme were also inhibited by SIC. SIC is the first biological inhibitor of the antibacterial action of SLPI to be described and may prove to be an important tool for investigating this activity in vivo. Inhibition of the antibacterial actions of SLPI and lysozyme would be advantageous to S. pyogenes in establishing colonization on mucosal surfaces, and we propose that this is the principal function of SIC.

Growth Characteristics of and Virulence Factor Production by Group A Streptococcus during Cultivation in Human Saliva

“…The role of Sic and SpeB in the growth of GAS in human saliva. GAS elaborates at least two extracellular proteins, SpeB and Sic, that have been shown to inhibit or inactivate the purified forms of antimicrobial peptides present in saliva (13,14,16,47). Sic is produced mainly by serotype M1 strains, whereas virtually all strains have the speB gene, although protein expression levels are variable (16,27,52).…”

Bioluminescence imaging reveals a significant role for complement in liver transduction following intravenous delivery of adenovirus

“…This is in contrast to other pathways by which pathogens exploit the complement system as a means to escape the host immune response. [18][19][20][21][22][23] For example, HIV has evolved to exploit complement pathways to survive and promote transmission to permissive cells. 24 In order for systemic delivery of Ad vectors to achieve clinical practicality, a better understanding of innate immunity is needed, including how complement influences the transduction process.…”

DRS Is Far Less Divergent than Streptococcal Inhibitor of Complement of Group A Streptococcus

“…Originally, SIC was characterized as an inhibitor of complement function that inhibits the cytolytic activity of the membrane attack complex. Subsequently, SIC was also shown to inhibit the antimicrobial activity of lysozyme, secretory leukocyte proteinase inhibitor, ␣-and ␤-defensins, and cathelicidin LL-37, which are the components of the innate immune system (1,3,7,9). The sic gene was initially found in serotypes M1 and M57 (1, 10); later, a variant of sic, distantly related sic (drs), was isolated from emm12 and emm55 strains (10).…”