The Streptococcus pyogenes hyaluronic acid capsule prevents neutrophil clearance, and greater insights into the streptococcal M protein as a vaccine candidate and driver of heart dysfunction
Abstract
Streptococcus pyogenes is a human-specific opportunistic pathogen that exploits an assortment of surface molecules to overcome host clearing mechanisms and cause a substantial burden of acute and chronic diseases worldwide. In the present work we utilize the M18 serotype S. pyogenes strain MGAS8232 to demonstrate that genomic deletion of thehyaluronic acid capsule significantly reduces bacterial densities in murine models of experimental nasopharyngeal and skin infections. We show that anti-Ly6G administration recovers the deteriorated burden by unencapsulated bacteria at both infection sites, indicating that capsule expression promotes resistance to neutrophil-mediated clearance during acute infections. We also evaluated the efficacy of serotype-specific immunity against the surface M protein and show that induction of serum M protein-specific IgG levels by monovalent M protein immunizations is not sufficient to protect mice from acute nasopharyngeal or skin challenges. Lastly, we implemented a recurring infection model to evaluate whether M protein expression is a possible driver of long-term cardiac complications. Multiple homologous infections with S. pyogenes MGAS8232 altered left ventricle filling dynamics and weakened ejection fractions by echocardiography compared to control inoculations with PBS or infection with S. pyogenes lacking its M protein, suggesting that M protein expression is directly associated with cardiac alterations. Together, this work provides deeper understandings on how S. pyogenes avoids innate clearance to establish superficial infections and reveals physiological insights on the development of cardiac impediments following multiple acute infections. This work has also provided valuable insights that will help guide future vaccine development strategies against this globally prominent pathogen.