Abstract
Highly pathogenic emm1 Streptococcus pyogenes strains secrete the multidomain Streptococcal inhibitor of complement (SIC) that binds and inactivates components of the innate immune response. We aimed to determine if naturally occurring or vaccine-induced antibodies to SIC are protective against invasive S. pyogenes infection. Immunisation with full-length SIC protected mice against systemic bacterial dissemination following intranasal or intramuscular infection with emm1 S. pyogenes. Vaccine-induced rabbit anti-SIC antibodies, but not naturally occurring human anti-SIC antibodies, enhanced bacterial clearance in an ex vivo whole-blood assay. SIC vaccination of both mice and rabbits resulted in antibody recognition of all domains of SIC, whereas naturally occurring human anti-SIC antibodies recognised the proline-rich region of SIC only. We, therefore, propose a model whereby natural infection with S. pyogenes generates non-protective antibodies against the proline-rich region of SIC, while vaccination with full-length SIC permits the development of protective antibodies against all SIC domains.
Highlights
Invasive disease caused by the human-specific pathogen, Streptococcus pyogenes, known as group A Streptococcus (GAS), has been increasing since the 1980s and is associated with mortality of ~20%1,2
There was a wide range of expression, there was no significant difference in the detected levels of Streptococcal inhibitor of complement (SIC) expression between invasive disease isolates, and non-invasive isolates (Fig. 1a)
Antibodies against SIC are widespread in populations worldwide[14,15,16], the role that these antibodies play in protection against infection with S. pyogenes remains unclear
Summary
Invasive disease caused by the human-specific pathogen, Streptococcus pyogenes, known as group A Streptococcus (GAS), has been increasing since the 1980s and is associated with mortality of ~20%1,2. Strains expressing the M1 protein, encoded by emm[1], are overrepresented amongst invasive isolates, and account for over 30% of cases of necrotising fasciitis and streptococcal toxic shock syndrome[3]. The Streptococcal inhibitor of complement (SIC) is an extracellular protein, almost uniquely expressed by emm[1] S. pyogenes, and is one of several virulence factors implicated in the propensity for emm[1] isolates to cause severe infection[4]. SIC was one of the 15 streptococcal proteins detected in pleural fluid from a child with empyema caused by emm[1] S. pyogenes, indicating that SIC is expressed at high levels during natural infection it may be degraded[13]
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