Auto-assembling detoxified staphylococcus aureus alpha-hemolysin mimicking the wild-type cytolytic toxin

Luigi Fiaschi, Benedetta Di Palo, Maria Scarselli, Clarissa Pozzi, Kelly Tomaszewski, Bruno Galletti, Vincenzo Nardi-Dei, Letizia Arcidiacono, Ravi P.N. Mishra, Elena Mori, Michele Pallaoro, Fabiana Falugi, Antonina Torre, Maria Rita Fontana, Marco Soriani, Juliane Bubeck Wardenburg, Guido Grandi, Rino Rappuoli, Ilaria Ferlenghi, Fabio Bagnoli

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Staphylococcus aureus alpha-hemolysin (Hla) assembles into heptameric pores on the host cell membrane, causing lysis, apoptosis, and junction disruption. Herein, we present the design of a newly engineered S. aureus alpha-toxin, HlaPSGS, which lacks the predicted membrane-spanning stem domain. This protein is able to form heptamers in aqueous solution in the absence of lipophilic substrata, and its structure, obtained by transmission electron microscopy and single-particle reconstruction analysis, resembles the cap of the wild-type cytolytic Hla pore. HlaPSGS was found to be impaired in binding to host cells and to its receptor ADAM10 and to lack hemolytic and cytotoxic activity. Immunological studies using human sera as well as sera from mice convalescent from S. aureus infection suggested that the heptameric conformation of HlaPSGS mimics epitopes exposed by the cytolytic Hla pore during infection. Finally, immunization with this newly engineered Hla generated high protective immunity against staphylococcal infection in mice. Overall, this study provides unprecedented data on the natural immune response against Hla and suggests that the heptameric HlaPSGS is a highly valuable vaccine candidate against S. aureus.

Original languageEnglish
Pages (from-to)442-450
Number of pages9
JournalClinical and Vaccine Immunology
Volume23
Issue number6
DOIs
StatePublished - Jun 2016

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    Fiaschi, L., Di Palo, B., Scarselli, M., Pozzi, C., Tomaszewski, K., Galletti, B., Nardi-Dei, V., Arcidiacono, L., Mishra, R. P. N., Mori, E., Pallaoro, M., Falugi, F., Torre, A., Fontana, M. R., Soriani, M., Wardenburg, J. B., Grandi, G., Rappuoli, R., Ferlenghi, I., & Bagnoli, F. (2016). Auto-assembling detoxified staphylococcus aureus alpha-hemolysin mimicking the wild-type cytolytic toxin. Clinical and Vaccine Immunology, 23(6), 442-450. https://doi.org/10.1128/CVI.00091-16