How strep bacteria outsmart your immune system and why it matters for treatment

In a recent study published in the journal Nature Communications, researchers report that the heterogeneity of Group A streptococcal infections and the transition of local to systemic infections occurs along with alterations of the immunoglobulin G (IgG) homeostasis by the pathogen.

Study: Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections. Image Credit: Jezper / Shutterstock.com

Background

Group A streptococcus, or Streptococcus pyogenes, causes local and systemic broad-spectrum infections in humans. These infections are associated with high morbidity and mortality rates, with approximately 18 million severe cases and 500,000 deaths reported every year.

In terms of disease severity, tissue tropism, and the sequelae post-infection, Group A streptococcal infections exhibit substantial heterogeneity. Localized throat or skin infections that result in pharyngitis or impetigo, which are often responsive to treatment with antimicrobials, sometimes progress into conditions such as necrotizing fasciitis and sepsis that can be life-threatening.

The sequelae following Group A streptococcal infections also vary more and consist of immune-mediated disorders such as acute rheumatic fever and glomerulonephritis. Group A streptococcal infections are often severe due to the ability of S. pyogenes to circumvent the defense mechanisms of the host and evade immunosurveillance.

S. pyogenes has developed numerous mechanisms to alter the structure and function of IgG to avoid antibody-mediated immune responses. Given the heterogeneity and severity of Group A streptococcal infections, it is essential to understand the factors and mechanisms that determine bacterial virulence.

About the study

In the present study, the researchers use a combination of animal model experiments and glycoproteomic and proteomic readouts to examine alterations to IgG homeostasis in Group A streptococcal infections. They built on their previous study, which showed that deglycosylated IgG accumulates in the tissues and body fluids of individuals with Group A streptococcal infections and that mouse models could be used to recapitulate this finding to understand the mechanisms underlying these infections.

The previous study used a selected reaction monitoring mass spectrometry approach to determine the accumulation of IgG degradation products. Despite being a highly sensitive analytical approach, this method was limited in its ability to monitor the changes in all IgG isoforms. Therefore, the present study used a data-dependent acquisition mass spectrometry approach, along with stepped high-energy collisional dissociation, to effectively determine site-specific differences in the IgG glycopeptide.

Group A streptococcus circumvents immune responses through binding to the IgG fragment crystallizable (Fc) region, which prevents opsonization and phagocytosis of bacteria. The bacteria also secrete two proteases that cleave IgG and degrade IgG antibodies and a bacterial glycan hydrolase called EndoS that deglycosylates IgG. The direct role of EndoS in the various IgG phenotypes during Group A streptococcal infections was also examined.

Plasma samples from murine models were subjected to quantitative proteomic analyses to determine whether other structural and functional changes in IgG and other proteins occurred in parallel with glycan degradation. To explore whether exogenously administered IgG was also cleaved and inactivated by the upregulation of the protease and EndoS activity, mice were administered a pharmaceutical-grade mixture of IgG and challenged subcutaneously with Group A streptococcus. Plasma samples obtained from these treated mice were then subjected to glycoproteomic analysis.

Study findings

The enzymatic degradation caused by Group A streptococcal infections in vivo resulted in the accumulation of cleaved IgG products in the plasma. Furthermore, altering IgG degradation was dependent on the route of inoculation and activities of the endoglycosidase EndoS and the bacterial protease IdeS, which are upregulated during Group A streptococcal infections.

Both the clinical heterogeneity observed during Group A streptococcal infections and the effectiveness of antibody-based therapies are influenced by the expression and upregulation of bacterial virulence factors. The host microenvironment also plays a partial role in modulating the virulence of Group A streptococcus. The alterations in IgG homeostasis, which can be attributed to the secretion of EndoS and IdeS, play an important role in the transition of local infections to systemic ones.

Bacteria virulence factors can also degrade the structure and modify the function of exogenously administered IgG, thus highlighting the need for preclinical evaluations of therapeutic antibodies before their administration. Modulating the efficacy of antibody-mediated treatment methods by bacterial virulence factors also emphasizes the need to conduct preclinical studies for other bacterial infections, especially pathogens that express similar protease and endoglycosidases, such as S. dysgalactiae and E. faecalis.

Conclusions

Bacterial virulence factors, especially proteases such as IdeS and endoglycosidases like EndoS, play an important role in the pathogenesis of Group A streptococcal infections. These virulence factors also degrade exogenously administered IgG in vivo, thus indicating that they can affect the effectiveness of antibody-mediated therapy for Group A streptococcal infections.