Native Human Antibody to Shr Promotes Mice Survival After Intraperitoneal Challenge With Invasive Group A...

Area of Science:

• Microbiology
• Immunology
• Vaccinology

Background:

• Group A Streptococcus (GAS) infections pose a significant health burden, with vaccine development actively pursued for decades.
• The GAS surface receptor Shr is crucial for heme uptake and represents a key target for developing immunotherapies.
• Human monoclonal antibodies (mAbs) against Shr were isolated to evaluate their potential in combating GAS.

Purpose of the Study:

• To isolate and characterize human monoclonal antibodies (mAbs) against the Group A Streptococcus (GAS) Shr surface receptor.
• To assess the efficacy of these mAbs in vitro and in vivo models of GAS infection.
• To elucidate the mechanism of action for antibody-mediated protection against GAS.

Main Methods:

• Single B-lymphocyte screening was employed to discover mAbs TRL186 and TRL96.
• Antibody interactions with GAS cells, proteins, and peptides were analyzed.
• In vitro assays assessed bacterial killing and heme uptake; in vivo studies evaluated prophylactic and therapeutic efficacy in mouse models.

Main Results:

• Both TRL186 and TRL96 bound to GAS cells, targeting different domains of the Shr receptor.
• TRL186 significantly improved survival in mice challenged with GAS, both prophylactically and therapeutically.
• TRL186 demonstrated an ability to impede heme binding to Shr and inhibit GAS growth on hemoglobin.

Conclusions:

• Interference with iron acquisition is a critical mechanism for TRL186's efficacy against GAS.
• Antibody-based immunotherapy targeting heme uptake proteins is a viable strategy for combating streptococcal infections.
• This study provides a strong foundation for developing novel immunotherapies against GAS.