Microbial Manipulation of Antibody Effector Functions

Abstract

In order to evade host immune mechanisms, many bacteria secrete immunomodulatory enzymes. Streptococcus pyogenes, one of the most common human pathogens, secretes a large endoglycosidase, EndoS, which removes carbohydrates in a highly specific manner from IgG antibodies. This renders antibodies incapable of eliciting host effector functions through either complement or Fc gamma receptors, providing the bacteria with a survival advantage. On account of this antibody-specific modifying activity, EndoS is currently being developed as a promising injectable therapeutic for autoimmune diseases that rely on autoantibodies. Additionally, EndoS is a key enzyme used in the chemoenzymatic synthesis of homogenously glycosylated antibodies with tailored Fc gamma receptor-mediated effector functions. Despite the tremendous utility of this enzyme, the molecular basis of EndoS specificity for, and processing of, IgG antibodies has remained poorly understood. In this seminar, I will describe our recent X-ray crystal structure of EndoS and a model of its encounter complex with its substrate, the IgG1 Fc domain Additionally, I will discuss how the EndoS structure provides a framework from which novel endoglycosidases could be engineered for additional clinical and biotechnological applications.