Insights into the Molecular Determinants of Staphylococcus aureus α-toxin Cytotoxicity: Characterizing Factors Behind Interindividual Variability of Infection Outcome

Abstract

Staphylococcus aureus is a major human pathogen that colonizes approximately 30% of the total human population. To ensure its survival within the host, S. aureus produces a large variety of virulence factors, among which α-toxin is studied most. Existing studies mostly focus on one specific disease or factor that modulates the sensitivity of people to α-toxin cytotoxicity but often overlook interplay of multiple determinants. Therefore, the aim of this thesis is to create a comprehensive overview of the current understanding of the molecular determinants of α-toxin cytotoxicity. Host factors that determine α-toxin cytotoxicity include the overall broad immunity and genetic background of a human individual. Broad immunity refers to the status of the host's immune system, the amount of neutralizing antibodies, and whether an individual has been vaccinated. Additionally, genetic deficiencies such as OTULIN haploinsufficiency and ATG16L1 might make individuals more vulnerable to α-toxin cytotoxicity. Environmental factors include the pure environment in and outside the body which might favor α-toxin exposure, production, and binding. Furthermore, exposure to different S. aureus strains affects α-toxin cytotoxicity depending on how efficiently each strain produces α-toxin. CA-MRSA classified strains generally produce more α-toxin and can therefore have more cytotoxic effects compared to HA-MRSA and LA-MRSA classified strains. More knowledge about all the different host and environmental factors that determine α-toxin cytotoxicity may provide a better indication of an individual's risk of developing severe symptoms during S. aureus infection. Additionally, a comprehensive overview of these factors may reveal new insights that could improve therapeutic interventions, prevent severe infection symptoms, and guide the development of more effective vaccines.