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Staphylococcus aureus is one of the commonly encountered bacteria of the human microbiome. Although mostly a seemingly harmless commensal microbe, S. aureus can act as an invasive pathogen with seriously devastating effects on its host’s health and wellbeing. A wide range of infections caused by this bacterium has been reported to affect diverse parts of the human body, including the skin, soft tissues and bones, as well as important organs like the heart, kidneys and lungs. Particularly, S. aureus is infamous for being a major causative agent of respiratory tract infections that may escalate up to necrotizing pneumonia. Due to its clinical relevance, this pathogen has been intensively studied for many years. Nonetheless, further research in this field is still needed, because of the high capacity of S. aureus to evolve drug resistance, its high genomic plasticity and adaptability and, not in the last place, the plethora of niches within the human body where it can thrive and survive. In this regard, there are still many uncertainties concerning the specific adaptations carried out by S. aureus during colonization and infection of the human body, the transition between both stages, and upon the invasion of different types of host cells. To shed more light on some of these adaptations, the research described in this thesis has employed in vitro models of infection that mimic particular conditions during the infectious process with special focus on the lung epithelium. The adaptations displayed by S. aureus were monitored using advanced proteomics. Furthermore, the analyses documented in this thesis included S. aureus strains with diverse backgrounds and epidemiology to take into account the genetic diversity encountered in this species.
The bacterium Staphylococcus aureus is a notorious pathogen that causes dangerous and difficult-to-treat infections. This applies especially to methicillin-resistant S. aureus, better known as MRSA. MRSA infections were originally associated with healthcare settings as a consequence of clinical antibiotic therapy. However, in recent years MRSA infections have become more common among healthy individuals in the community. The community-associated (CA-)MRSA lineages are generally more aggressive than hospital-associated (HA-) lineages. Therefore, it is alarming that such CA-MRSA lineages are now emerging in hospitals. This raises the fundamental question of how CA-MRSA adapts to this new niche. Further, since the originally distinguishing features of CA- and HA-MRSA are losing discriminative value, it is important from a healthcare perspective to identify novel distinctive markers for early recognition and elimination of hospital-adapted CA-MRSA. In the present PhD research, these challenges were tackled with a ‘multi-omics’ approach focused on the USA300 lineage of MRSA, originally identified as CA, but now also causing hospital outbreaks. The results show that hospital-adapted USA300 isolates produce an altered spectrum of virulence factors, changed their metabolism, and exploit human immune cells as a protective environment against antibiotics. Importantly, hospital-adapted CA-MRSA strains can be recognized through distinctive patterns of gene expression and secreted virulence factors. Altogether, these observations show that the epidemic behaviour of MRSA is a multi-factorial trait, and they provide new insights into the missing links between epidemiology and pathophysiology of S. aureus. Moreover, they highlight the benefits of multi-omics technologies for protecting patients and frail individuals against the aggressive CA-MRSA.