Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model.
Previous efforts towards S. aureus vaccine development have largely focused on cell surface antigens to induce opsonophagocytic killing aimed at providing sterile immunity, a concept successfully applied to other Gram-positive pathogens such as Streptococcus pneumoniae. However, these approaches hav...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3676412?pdf=render |
| _version_ | 1819268073849356288 |
|---|---|
| author | Hatice Karauzum Rajan P Adhikari Jawad Sarwar V Sathya Devi Laura Abaandou Christian Haudenschild Mahta Mahmoudieh Atefeh R Boroun Hong Vu Tam Nguyen Kelly L Warfield Sergey Shulenin M Javad Aman |
| author_facet | Hatice Karauzum Rajan P Adhikari Jawad Sarwar V Sathya Devi Laura Abaandou Christian Haudenschild Mahta Mahmoudieh Atefeh R Boroun Hong Vu Tam Nguyen Kelly L Warfield Sergey Shulenin M Javad Aman |
| author_sort | Hatice Karauzum |
| collection | DOAJ |
| description | Previous efforts towards S. aureus vaccine development have largely focused on cell surface antigens to induce opsonophagocytic killing aimed at providing sterile immunity, a concept successfully applied to other Gram-positive pathogens such as Streptococcus pneumoniae. However, these approaches have largely failed, possibly in part due to the remarkable diversity of the staphylococcal virulence factors such as secreted immunosuppressive and tissue destructive toxins. S. aureus produces several pore-forming toxins including the single subunit alpha hemolysin as well as bicomponent leukotoxins such as Panton-Valentine leukocidin (PVL), gamma hemolysins (Hlg), and LukED. Here we report the generation of highly attenuated mutants of PVL subunits LukS-PV and LukF-PV that were rationally designed, based on an octameric structural model of the toxin, to be deficient in oligomerization. The attenuated subunit vaccines were highly immunogenic and showed significant protection in a mouse model of S. aureus USA300 sepsis. Protection against sepsis was also demonstrated by passive transfer of rabbit immunoglobulin raised against LukS-PV. Antibodies to LukS-PV inhibited the homologous oligomerization of LukS-PV with LukF-PV as well heterologous oligomerization with HlgB. Importantly, immune sera from mice vaccinated with the LukS mutant not only inhibited the PMN lytic activity produced by the PVL-positive USA300 but also blocked PMN lysis induced by supernatants of PVL-negative strains suggesting a broad protective activity towards other bicomponent toxins. These findings strongly support the novel concept of an anti-virulence, toxin-based vaccine intended for prevention of clinical S. aureus invasive disease, rather than achieving sterile immunity. Such a multivalent vaccine may include attenuated leukotoxins, alpha hemolysin, and superantigens. |
| first_indexed | 2024-12-23T21:27:16Z |
| format | Article |
| id | doaj.art-faaf2802732c492faa044e7139f76413 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T21:27:16Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-faaf2802732c492faa044e7139f764132022-12-21T17:30:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6538410.1371/journal.pone.0065384Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model.Hatice KarauzumRajan P AdhikariJawad SarwarV Sathya DeviLaura AbaandouChristian HaudenschildMahta MahmoudiehAtefeh R BorounHong VuTam NguyenKelly L WarfieldSergey ShuleninM Javad AmanPrevious efforts towards S. aureus vaccine development have largely focused on cell surface antigens to induce opsonophagocytic killing aimed at providing sterile immunity, a concept successfully applied to other Gram-positive pathogens such as Streptococcus pneumoniae. However, these approaches have largely failed, possibly in part due to the remarkable diversity of the staphylococcal virulence factors such as secreted immunosuppressive and tissue destructive toxins. S. aureus produces several pore-forming toxins including the single subunit alpha hemolysin as well as bicomponent leukotoxins such as Panton-Valentine leukocidin (PVL), gamma hemolysins (Hlg), and LukED. Here we report the generation of highly attenuated mutants of PVL subunits LukS-PV and LukF-PV that were rationally designed, based on an octameric structural model of the toxin, to be deficient in oligomerization. The attenuated subunit vaccines were highly immunogenic and showed significant protection in a mouse model of S. aureus USA300 sepsis. Protection against sepsis was also demonstrated by passive transfer of rabbit immunoglobulin raised against LukS-PV. Antibodies to LukS-PV inhibited the homologous oligomerization of LukS-PV with LukF-PV as well heterologous oligomerization with HlgB. Importantly, immune sera from mice vaccinated with the LukS mutant not only inhibited the PMN lytic activity produced by the PVL-positive USA300 but also blocked PMN lysis induced by supernatants of PVL-negative strains suggesting a broad protective activity towards other bicomponent toxins. These findings strongly support the novel concept of an anti-virulence, toxin-based vaccine intended for prevention of clinical S. aureus invasive disease, rather than achieving sterile immunity. Such a multivalent vaccine may include attenuated leukotoxins, alpha hemolysin, and superantigens.http://europepmc.org/articles/PMC3676412?pdf=render |
| spellingShingle | Hatice Karauzum Rajan P Adhikari Jawad Sarwar V Sathya Devi Laura Abaandou Christian Haudenschild Mahta Mahmoudieh Atefeh R Boroun Hong Vu Tam Nguyen Kelly L Warfield Sergey Shulenin M Javad Aman Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model. PLoS ONE |
| title | Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model. |
| title_full | Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model. |
| title_fullStr | Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model. |
| title_full_unstemmed | Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model. |
| title_short | Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model. |
| title_sort | structurally designed attenuated subunit vaccines for s aureus luks pv and lukf pv confer protection in a mouse bacteremia model |
| url | http://europepmc.org/articles/PMC3676412?pdf=render |
| work_keys_str_mv | AT haticekarauzum structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT rajanpadhikari structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT jawadsarwar structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT vsathyadevi structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT lauraabaandou structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT christianhaudenschild structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT mahtamahmoudieh structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT atefehrboroun structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT hongvu structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT tamnguyen structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT kellylwarfield structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT sergeyshulenin structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel AT mjavadaman structurallydesignedattenuatedsubunitvaccinesforsaureuslukspvandlukfpvconferprotectioninamousebacteremiamodel |