How staphylococcal protein A blocks IgG effector functions: A golden way to evade phagocytosis

Abstract

Antibiotic resistance is a major problem for public health. Staphylococcus aureus, commonly known as “multi-drug resistant bacterium” or simply as “super bug”, is one of the pathogens for which new antibiotics and other therapeutic options are urgently needed. S. aureus can cause mild to life-threatening diseases that include skin and soft tissue infections, pneumonia, infective endocarditis, osteomyelitis and sepsis. Although our immune defenses protect our body from invading bacteria, some pathogens, like S. aureus, have evolved strategies to evade the host immune system. One particularly important immune evasion factor of S. aureus is staphylococcal protein A (SpA). SpA binds to the constant region of antibodies to prevent phagocytic cells from recognizing S. aureus. Antibodies have a variable and a constant region. The variable region can recognize antigens that are secreted by the bacteria, or that are exposed on their surfaces. When antibodies bind to surface antigens via their variable region, their constant region can trigger bacterial clearance by inducing complement activation and by interacting directly with immune cells, like neutrophils. Decoration of the bacteria with antibodies and complement proteins is essential for their recognition by phagocytic cells. Upon recognition, these cells engulf and kill the bacteria intracellularly. In this thesis, we focused on understanding how SpA, by binding to the constant region of antibodies, interferes with antibody- and complement-mediated phagocytosis of S. aureus. The here gained knowledge provides a rationale for optimizing antibody therapies against S. aureus, as alternatives to antibiotics.