Abigail Adaramola

Introduction. Streptococcus pyogenes is a gram-positive human pathogen that is known to cause a range of diseases from mild to life threatening invasive infections.¹ Every year, more than 700 million S. pyogenes infections occur worldwide with more than 500,000 deaths.¹ Due to the burden of infection worldwide, development of a vaccine is very much needed. The ability of S. pyogenes to cause infection is dependent on several pathogenic methods including evasion of the complement system. Several studies have investigated the different mechanisms by which S. pyogenes interacts with IgG and other human serum proteins to evade the complement system. By having a better understanding of how these interactions take place we can create effective therapeutics against S. pyogenes. Methods. Surface plasmon resonance (SPR) was used to detect molecular interactions between virulence factors of S. pyogenes and human serum proteins. Enzyme-linked immunosorbent assay (ELISA) were used to quantify and detect the activity of human serum proteins and their interactions with virulence proteins of S. pyogenes. An in vivo model was developed to examine these interactions using transgenic mice expressing human serum proteins. Results. Protein H, a virulence surface protein of S. pyogenes, binds both IgG and C4b binding protein (C4BP), a complement inhibitor, as a method to evade complement.^1,2 it was discovered that, the presence of IgG bound to protein H will increase binding of C4BP to protein H.^1,2 Another mechanism involves Endopeptidase O (PepO), a secreted virulence factor, binding and inactivating C1q, a complement initiator protein.³ It was found that as pH decreases (pH lower than 7.0) PepO was found to have a higher affinity for C1q compared to IgG.³ One study was able to create a novel immunotherapeutic chimeric protein against S. pyogenes by exploiting its interactions patterns with human serum proteins. The chimeric protein showed enhanced ability to activate complement pathways and reduce bacterial blood burden, indicating its possible use as an adjunct therapy to S. pyogenes infection.⁴ Conclusion. There are multiple mechanisms by which S. pyogenes interacts with IgG and other serum proteins to evade complement. An increased understanding of these interactions will aid in the development of better therapies and eventual vaccines to fight against S. pyogenes infection.

1. Ermert D, Weckel A, Magda M, et al Human IgG Increases Virulence of Streptococcus pyogenes through Complement Evasion. J Immunol. 2018;200(10):3495-3505. doi:10.4049/jimmunol.1800090
2. Ermert D, Laabei M, Weckel A, et al The Molecular Basis of Human IgG-Mediated Enhancement of C4b-Binding Protein Recruitment to Group A Streptococcus. Front Immunol. 2019;10:1230. Published 2019 Jun 4. doi:10.3389/fimmu.2019.01230
3. Honda-Ogawa M, Sumitomo T, Mori Y, et al Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q. J Biol Chem. 2017;292(10):4244-4254. doi:10.1074/jbc.M116.749275
4. Blom AM, Magda M, Kohl L, et al Factor H-IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial Pathogen Streptococcus pyogenes. J Immunol. 2017;199(11):3828-3839. doi:10.4049/jimmunol.1700426