Staphylococcus aureus membrane vesicles: an evolving story

Abstract

Staphylococcus aureus is an important bacterial pathogen that causes a wide variety of human diseases in community and hospital settings. S. aureus employs a diverse array of virulence factors, both surface-associated and secreted, to promote colonization, infection, and immune evasion. Over the past decade, a growing body of research has shown that S. aureus generates extracellular membrane vesicles (MVs) that package a variety of bacterial components, many of which are virulence factors. In this review, we summarize recent advances in our understanding of S. aureus MVs and highlight their biogenesis, cargo, and potential role in the pathogenesis of staphylococcal infections. Lastly, we present some emerging questions in the field.

Keywords: Staphylococcus aureus; biogenesis; cargo; extracellular membrane vesicles; vaccine; virulence factors.

Figure 1.

S. aureus MVs visualized by transmission electron microscopy. A. An ultrathin section of S. aureus JE2 reveals MVs (indicated by a red arrow) released from the bacterial cell (Adapted from [17]). B. A representative micrograph of MVs (indicated by white arrows) purified from S. aureus MN8 cultures harvested in the post-exponential growth phase (Adapted from [13]).

Figure 2.

A model for the generation of MVs from the S. aureus cell envelope. The Gram-positive bacterium S. aureus has a cytoplasmic membrane containing membrane proteins, lipoteichoic acids, and lipoproteins. The cell wall is comprised of highly cross-linked peptidoglycan, wall teichoic acid, and surface proteins. S. aureus MVs are generated from the cytoplasmic membrane, a process that is modulated by the activity of PSM peptides and cellular turgor pressure. PSMs have surfactant-like activity, enhancing membrane fluidity and curvature. Extruded MVs must traverse the highly cross-linked layers of peptidoglycan before release, and this process is promoted by S. aureus peptidoglycan hydrolases (autolysins). Figure was generated in BioRender.

Figure 3.

Current model summarizing interactions between S. aureus MVs and the host cell. S. aureus releases both soluble molecules (e.g., virulence factors) and MVs into the host environment. Unlike soluble molecules that can be inactivated by host neutralizing antibodies or hydrolytic enzymes, bacterial cargo within S. aureus MVs is protected from destruction by host factors. S. aureus MVs released from bacteria can induce host innate immune activation via the TLR2 receptor localized in the host cell membrane. MVs may be internalized into the host cell via endocytosis or membrane fusion and routed to the early endosome, followed by sorting to endolysosomes for degradation. S. aureus MVs carry multiple pore-forming toxins that could disrupt endosomal membranes and facilitate the escape of MVs to the host cytosol. The MV cargo released into the cell cytosol may be sensed by cytosolic innate immune receptors, such as inflammasomes, modulating innate immune responses that may lead to host cell death (e.g., pyroptosis). Figure was generated in BioRender.