How staphylococcal protein A blocks IgG effector functions

Abstract

About the title:The word "aureus", from Staphylococcus aureus comes from the Latin "aurum", which means gold. This is because of the yellow pigmentation that characterizes S. aureus colonies. Thus, the subtitle can be read in two ways: 1) this gold(en) pathogen uses staphylococcal protein A (SpA) as a tool to evade phagocytosis, 2) SpA is a golden/excellent tool that enables S. aureus to evade phagocytosis. About the cover: The cover is inspired by the Portuguese tiles but also by one of the main findings of the research described in this thesis: SpA prevents antibodies from clustering into groups of six. Antibody clustering on the bacterial surface is important for efficient clearance of the bacteria by immune cells. The function of SpA is depicted in the gold misplaced tile. 11 General introduction 1 Staphylococcus aureus (S. aureus) is a human pathogen that can live a commensal lifestyle in approximately 80% of the population. It can however also cause a wide range of infections including those of the skin, soft tissues, lungs, bones, joints, and endocardium. Antibiotics are considered the gold standard for treating S. aureus infections. However, most of the existing antibiotics are not effective against multidrug resistant S. aureus strains. In particular, methicillin-resistant S. aureus (MRSA) strains are associated with poor clinical outcomes. Thus, there is a clear need for alternative therapies to antibiotics. Great efforts have been made to develop active and passive immunization approaches targeting S. aureus, however, they have failed to show effectiveness in humans. The overreliance on animal models and the fact that S. aureus is equipped with a large array of virulence factors that include multiple immune evasion factors might explain this failure. One particularly important immune evasion factor of S. aureus is staphylococcal protein A (SpA). Staphylococcus aureusStaphylococcus aureus (S. aureus) was identified for the first time in 1880 by the Scottish surgeon Alexander Ogston (1844-1929) (1). Intrigued by the effect of antiseptics on the reduction of the mortality rate post-surgery, Ogston examined pus from abscesses under the microscope and found micrococci that rearranged in clusters that he named "staphylococcus" (from the Greek "staphyle" meaning bunch of grapes) (1). In 1886, the German surgeon Rosenbach isolated two staphylococcal strains and named the gold-pigmented strain as Staphylococcus aureus (from the Latin "aurum" meaning gold) (2). S. aureus is a Gram-positive bacterium that asymptomatically colonizes approximately 80% of human population. Persistent carriers (±20%) are usually colonized with a single strain of S. aureus, while intermittent carriers (±60%) can carry different S. aureus strains (3, 4). The anterior nares are the most frequent site of colonization, although S. aureus can also be found in other skin areas (3). S. aureus is also an opportunistic pathogen that can infect most of the tissues of the human body causing mild to life-threatening diseases that include skin and...