Rational Design of Toxoid Vaccine Candidates for <i>Staphylococcus aureus</i> Leukocidin AB (LukAB)
<i>Staphylococcus aureus</i> (SA) infections cause high mortality and morbidity in humans. Being central to its pathogenesis, <i>S. aureus</i> thwarts the host defense by secreting a myriad of virulence factors, including bicomponent, pore-forming leukotoxins. While all vacci...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-06-01
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| Series: | Toxins |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6651/11/6/339 |
| _version_ | 1811304988932046848 |
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| author | Shweta Kailasan Thomas Kort Ipsita Mukherjee Grant C. Liao Tulasikumari Kanipakala Nils Williston Nader Ganjbaksh Arundhathi Venkatasubramaniam Frederick W. Holtsberg Hatice Karauzum Rajan P. Adhikari M. Javad Aman |
| author_facet | Shweta Kailasan Thomas Kort Ipsita Mukherjee Grant C. Liao Tulasikumari Kanipakala Nils Williston Nader Ganjbaksh Arundhathi Venkatasubramaniam Frederick W. Holtsberg Hatice Karauzum Rajan P. Adhikari M. Javad Aman |
| author_sort | Shweta Kailasan |
| collection | DOAJ |
| description | <i>Staphylococcus aureus</i> (SA) infections cause high mortality and morbidity in humans. Being central to its pathogenesis, <i>S. aureus</i> thwarts the host defense by secreting a myriad of virulence factors, including bicomponent, pore-forming leukotoxins. While all vaccine development efforts that aimed at achieving opsonophagocytic killing have failed, targeting virulence by toxoid vaccines represents a novel approach to preventing mortality and morbidity that are caused by SA. The recently discovered leukotoxin LukAB kills human phagocytes and monocytes and it is present in all known <i>S. aureus</i> clinical isolates. While using a structure-guided approach, we generated a library of mutations that targeted functional domains within the LukAB heterodimer to identify attenuated toxoids as potential vaccine candidates. The mutants were evaluated based on expression, solubility, yield, biophysical properties, cytotoxicity, and immunogenicity, and several fully attenuated LukAB toxoids that were capable of eliciting high neutralizing antibody titers were identified. Rabbit polyclonal antibodies against the lead toxoid candidate provided potent neutralization of LukAB. While the neutralization of LukAB alone was not sufficient to fully suppress leukotoxicity in supernatants of <i>S. aureus</i> USA300 isolates, a combination of antibodies against LukAB, α-toxin, and Panton-Valentine leukocidin completely neutralized the cytotoxicity of these strains. These data strongly support the inclusion of LukAB toxoids in a multivalent toxoid vaccine for the prevention of <i>S. aureus</i> disease. |
| first_indexed | 2024-04-13T08:17:16Z |
| format | Article |
| id | doaj.art-c6f398503f794613afe09b6beeb975f9 |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-04-13T08:17:16Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-c6f398503f794613afe09b6beeb975f92022-12-22T02:54:45ZengMDPI AGToxins2072-66512019-06-0111633910.3390/toxins11060339toxins11060339Rational Design of Toxoid Vaccine Candidates for <i>Staphylococcus aureus</i> Leukocidin AB (LukAB)Shweta Kailasan0Thomas Kort1Ipsita Mukherjee2Grant C. Liao3Tulasikumari Kanipakala4Nils Williston5Nader Ganjbaksh6Arundhathi Venkatasubramaniam7Frederick W. Holtsberg8Hatice Karauzum9Rajan P. Adhikari10M. Javad Aman11Integrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USAIntegrated Biotherapeutics Inc., Rockville, MD 20850, USA<i>Staphylococcus aureus</i> (SA) infections cause high mortality and morbidity in humans. Being central to its pathogenesis, <i>S. aureus</i> thwarts the host defense by secreting a myriad of virulence factors, including bicomponent, pore-forming leukotoxins. While all vaccine development efforts that aimed at achieving opsonophagocytic killing have failed, targeting virulence by toxoid vaccines represents a novel approach to preventing mortality and morbidity that are caused by SA. The recently discovered leukotoxin LukAB kills human phagocytes and monocytes and it is present in all known <i>S. aureus</i> clinical isolates. While using a structure-guided approach, we generated a library of mutations that targeted functional domains within the LukAB heterodimer to identify attenuated toxoids as potential vaccine candidates. The mutants were evaluated based on expression, solubility, yield, biophysical properties, cytotoxicity, and immunogenicity, and several fully attenuated LukAB toxoids that were capable of eliciting high neutralizing antibody titers were identified. Rabbit polyclonal antibodies against the lead toxoid candidate provided potent neutralization of LukAB. While the neutralization of LukAB alone was not sufficient to fully suppress leukotoxicity in supernatants of <i>S. aureus</i> USA300 isolates, a combination of antibodies against LukAB, α-toxin, and Panton-Valentine leukocidin completely neutralized the cytotoxicity of these strains. These data strongly support the inclusion of LukAB toxoids in a multivalent toxoid vaccine for the prevention of <i>S. aureus</i> disease.https://www.mdpi.com/2072-6651/11/6/339Leukocidin<i>Staphylococcus aureus</i>LukABLukGHtoxin neutralizationpolyclonal antibodytoxoid vaccine |
| spellingShingle | Shweta Kailasan Thomas Kort Ipsita Mukherjee Grant C. Liao Tulasikumari Kanipakala Nils Williston Nader Ganjbaksh Arundhathi Venkatasubramaniam Frederick W. Holtsberg Hatice Karauzum Rajan P. Adhikari M. Javad Aman Rational Design of Toxoid Vaccine Candidates for <i>Staphylococcus aureus</i> Leukocidin AB (LukAB) Toxins Leukocidin <i>Staphylococcus aureus</i> LukAB LukGH toxin neutralization polyclonal antibody toxoid vaccine |
| title | Rational Design of Toxoid Vaccine Candidates for <i>Staphylococcus aureus</i> Leukocidin AB (LukAB) |
| title_full | Rational Design of Toxoid Vaccine Candidates for <i>Staphylococcus aureus</i> Leukocidin AB (LukAB) |
| title_fullStr | Rational Design of Toxoid Vaccine Candidates for <i>Staphylococcus aureus</i> Leukocidin AB (LukAB) |
| title_full_unstemmed | Rational Design of Toxoid Vaccine Candidates for <i>Staphylococcus aureus</i> Leukocidin AB (LukAB) |
| title_short | Rational Design of Toxoid Vaccine Candidates for <i>Staphylococcus aureus</i> Leukocidin AB (LukAB) |
| title_sort | rational design of toxoid vaccine candidates for i staphylococcus aureus i leukocidin ab lukab |
| topic | Leukocidin <i>Staphylococcus aureus</i> LukAB LukGH toxin neutralization polyclonal antibody toxoid vaccine |
| url | https://www.mdpi.com/2072-6651/11/6/339 |
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