The biogenesis of extracellular vesicles from Staphylococcus aureus and their application as a novel vaccine platform

Gram-positive bacteria secrete extracellular vesicles (EVs) that package diverse bacterial antigens and play key roles in bacterial pathogenesis. However, the mechanisms underlying EV production in Gram-positive bacteria are poorly understood. We purified and characterized EVs from a community-assoc...

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Bibliographic Details
Published inbioRxiv
Main Authors Wang, Xiaogang, Weidenmaier, Christopher, Lee, Jean C
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 28.01.2018
Subjects
Antigens
Autolysins
Biosynthesis
Cell walls
Cytolysins
Cytoplasmic membranes
Cytotoxicity
Drug resistance
Extracellular vesicles
Gram-positive bacteria
Histocompatibility antigen HLA
Immunogenicity
Lethality
Methicillin
Peptidoglycans
Permeability
Phenols
Proteins
Sepsis
Staphylococcus infections
Vaccines
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Summary:Gram-positive bacteria secrete extracellular vesicles (EVs) that package diverse bacterial antigens and play key roles in bacterial pathogenesis. However, the mechanisms underlying EV production in Gram-positive bacteria are poorly understood. We purified and characterized EVs from a community-associated methicillin-resistant Staphylococcus aureus isolate (USA300) and investigated mechanisms underlying EV production. Native EVs contained 165 proteins, including cytosolic, surface, and secreted proteins, autolysins, and numerous cytolysins. Staphylococcal alpha-type phenol-soluble modulins (surfactant-like peptides) promoted EV biogenesis, presumably by acting at the cytoplasmic membrane, whereas peptidoglycan crosslinking and autolysin activity were found to increase EV production by altering the permeability of the staphylococcal cell wall. To address the immunogenicity of EVs, we created engineered EVs (eng-EVs) by expressing detoxified proteins HlaH35L and LukE in EVs generated from a nontoxic S. aureus agr spa mutant. Eng-EVs exhibited no cytotoxicity in vitro, and mice immunized with the eng-EVs produced toxin-neutralizing antibodies and showed reduced lethality in a mouse sepsis model. Our study reveals novel mechanisms underlying S. aureus EV production and highlights the usefulness of EVs as a novel S. aureus vaccine platform.
DOI:10.1101/255273