**7.** *S. aureus***-EVs and host cells specificity**

#### **7.1** *S. aureus***-EVs strain specificity**

Cytotoxicity and immunomodulation of EVs towards host cells vary according to the *S. aureus* strain and host cell line studied since both can have specific

*Extracellular Vesicles and Their Role in* Staphylococcus aureus *Resistance and Virulence DOI: http://dx.doi.org/10.5772/intechopen.96023*

characteristics. As virulence factors vary from an *S. aureus* strain to another, so does the cargo of EVs. This affects cytotoxicity and host cell response to EVs contact. It was demonstrated that the presence of α-hemolysin in EVs is directly related to host cell death, and EVs from α-hemolysin-negative strains have very low or no cytotoxic effect on different cell types [30, 64]. Similarly, EVs from M060 *S. aureus* strain containing exfoliative toxin A (ETA) were highly cytotoxic towards HEp-2 cells, contrary to EVs purified from three other *S. aureus* isolates that lacked the ETA protein [31]. Furthermore, it was also demonstrated that EVs from *S. aureus* ATCC 25923 induces a stronger immune response in HaCaT cells than that of M060 EVs at the same concentrations [65]. These data show that EVs from different *S. aureus* strains indeed have different effects on host cells.

#### **7.2 Host cell lines specificity**

On the other hand, the cell lines used *in vitro* also have different responses reflecting differences in host cells-EVs interactions, which result in variable cytotoxicity, and immunomodulation levels. EVs derived from *S. aureus* subsp. *aureus* Rosenbach MSSA476 induced extensive cell death in human neutrophils and THP-1 cells, while it had very low cytotoxicity in HaCaT at the same concentrations [69]. In another study, *S. aureus* JE2 EVs were showed to be less cytotoxic to airway epithelial cells (A549) than to erythrocytes and neutrophil-like HL60 cells [40]. As another example, after exposure to ATCC 14458 *S. aureus* EVs, alveolar macrophages produced TNF-α and IL-6, while A549 cells produced only IL-6 [35]. Together, these findings show that EVs' role in host cell toxicity and immune response is strongly affected by the variations in EV cargo, which itself vary from an *S. aureus* strains to another, and to variations in molecular and physiological characteristics of the host cell types.
