Breaking the barriers: how Staphylococcus aureus reaches different human host niches

The opportunistic pathogen Staphylococcus aureus is part of the human microbiome, the skin and mucosa being its best-characterized reservoirs. Carriage and colonization rates of this bacterium vary in different human populations but, on average, S. aureus colonizes ~20% of all individuals asymptomatically. Unfortunately, S. aureus is notorious for causing severe invasive diseases in the human host, manifesting itself with different epidemiology and pathophysiology. The efficacy of available antimicrobial treatments varies depending on the presence of multi-drug resistant strains, the type of infection, and escape of the bacteria to different protective (intracellular) host niches. Today, there are still many uncertainties about the roles of different niches in the human body, about the roles of different human cells that facilitate S. aureus survival, and about the precise determinants for the epidemiological behaviour of S. aureus. The research described in this dissertation was aimed at shedding more light on poorly understood mechanisms employed by different S. aureus lineages to thrive in the human body and on the human host responses towards S. aureus in the context of the gut, the bloodstream, the endothelium and the lung epithelium. These objectives were achieved by following different approaches, including comparative genomics, transcriptomics and proteomics, combined with in vivo and in vitro infection models. The results show that the infectious behaviour of S. aureus depends on multiple bacterial traits, including virulence factors, metabolic adaptations and fitness. Importantly, however, S. aureus can only unfold its full pathogenic potential when critical barriers in the human body are compromised