Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization
Staphylococcus aureus carries an exceptional repertoire of virulence factors that aid in immune evasion. Previous single-target approaches for S. aureus-specific vaccines and monoclonal antibodies (mAbs) have failed in clinical trials due to the multitude of virulence factors released during infecti...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2022.2083467 |
| _version_ | 1818251296174505984 |
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| author | Shweta Kailasan Ravi Kant Madeleine Noonan-Shueh Tulasikumari Kanipakala Grant Liao Sergey Shulenin Daisy W. Leung Richard A. Alm Rajan P. Adhikari Gaya K. Amarasinghe Michael L. Gross M. Javad Aman |
| author_facet | Shweta Kailasan Ravi Kant Madeleine Noonan-Shueh Tulasikumari Kanipakala Grant Liao Sergey Shulenin Daisy W. Leung Richard A. Alm Rajan P. Adhikari Gaya K. Amarasinghe Michael L. Gross M. Javad Aman |
| author_sort | Shweta Kailasan |
| collection | DOAJ |
| description | Staphylococcus aureus carries an exceptional repertoire of virulence factors that aid in immune evasion. Previous single-target approaches for S. aureus-specific vaccines and monoclonal antibodies (mAbs) have failed in clinical trials due to the multitude of virulence factors released during infection. Emergence of antibiotic-resistant strains demands a multi-target approach involving neutralization of different, non-overlapping pathogenic factors. Of the several pore-forming toxins that contribute to S. aureus pathogenesis, efforts have largely focused on mAbs that neutralize α-hemolysin (Hla) and target the receptor-binding site. Here, we isolated two anti-Hla and three anti-Panton-Valentine Leukocidin (LukSF-PV) mAbs, and used a combination of hydrogen deuterium exchange mass spectrometry (HDX-MS) and alanine scanning mutagenesis to delineate and validate the toxins’ epitope landscape. Our studies identified two novel, neutralizing epitopes targeted by 2B6 and CAN6 on Hla that provided protection from hemolytic activity in vitro and showed synergy in rodent pneumonia model against lethal challenge. Of the anti-LukF mAbs, SA02 and SA131 showed specific neutralization activity to LukSF-PV while SA185 showed cross-neutralization activity to LukSF-PV, γ-hemolysin HlgAB, and leukotoxin ED. We further compared these antigen-specific mAbs to two broadly neutralizing mAbs, H5 (targets Hla, LukSF-PV, HlgAB, HlgCB, and LukED) and SA185 (targeting LukSF-PV, HlgAB, and LukED), and identified molecular level markers for broad-spectrum reactivity among the pore-forming toxins by HDX-MS. To further underscore the need to target the cross-reactive epitopes on leukocidins for the development of broad-spectrum therapies, we annotated Hla sequences isolated from patients in multiple countries for genomic variations within the perspective of our defined epitopes. |
| first_indexed | 2024-12-12T16:06:01Z |
| format | Article |
| id | doaj.art-536d0a35d34246f88a85754222c857ae |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-12-12T16:06:01Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-536d0a35d34246f88a85754222c857ae2022-12-22T00:19:17ZengTaylor & Francis GroupmAbs1942-08621942-08702022-12-0114110.1080/19420862.2022.2083467Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralizationShweta Kailasan0Ravi Kant1Madeleine Noonan-Shueh2Tulasikumari Kanipakala3Grant Liao4Sergey Shulenin5Daisy W. Leung6Richard A. Alm7Rajan P. Adhikari8Gaya K. Amarasinghe9Michael L. Gross10M. Javad Aman11Integrated BioTherapeutics, Rockville, USADepartment of Chemistry, Washington University in St. Louis, St. Louis, USAIntegrated BioTherapeutics, Rockville, USAIntegrated BioTherapeutics, Rockville, USAIntegrated BioTherapeutics, Rockville, USAIntegrated BioTherapeutics, Rockville, USADepartment of Medicine, Washington University in St. Louis, St. Louis, USABoston University School of Law, Boston University, Boston, USAIntegrated BioTherapeutics, Rockville, USADepartment of Pathology and Immunology, Washington University in St. Louis, St. Louis, USADepartment of Chemistry, Washington University in St. Louis, St. Louis, USAIntegrated BioTherapeutics, Rockville, USAStaphylococcus aureus carries an exceptional repertoire of virulence factors that aid in immune evasion. Previous single-target approaches for S. aureus-specific vaccines and monoclonal antibodies (mAbs) have failed in clinical trials due to the multitude of virulence factors released during infection. Emergence of antibiotic-resistant strains demands a multi-target approach involving neutralization of different, non-overlapping pathogenic factors. Of the several pore-forming toxins that contribute to S. aureus pathogenesis, efforts have largely focused on mAbs that neutralize α-hemolysin (Hla) and target the receptor-binding site. Here, we isolated two anti-Hla and three anti-Panton-Valentine Leukocidin (LukSF-PV) mAbs, and used a combination of hydrogen deuterium exchange mass spectrometry (HDX-MS) and alanine scanning mutagenesis to delineate and validate the toxins’ epitope landscape. Our studies identified two novel, neutralizing epitopes targeted by 2B6 and CAN6 on Hla that provided protection from hemolytic activity in vitro and showed synergy in rodent pneumonia model against lethal challenge. Of the anti-LukF mAbs, SA02 and SA131 showed specific neutralization activity to LukSF-PV while SA185 showed cross-neutralization activity to LukSF-PV, γ-hemolysin HlgAB, and leukotoxin ED. We further compared these antigen-specific mAbs to two broadly neutralizing mAbs, H5 (targets Hla, LukSF-PV, HlgAB, HlgCB, and LukED) and SA185 (targeting LukSF-PV, HlgAB, and LukED), and identified molecular level markers for broad-spectrum reactivity among the pore-forming toxins by HDX-MS. To further underscore the need to target the cross-reactive epitopes on leukocidins for the development of broad-spectrum therapies, we annotated Hla sequences isolated from patients in multiple countries for genomic variations within the perspective of our defined epitopes.https://www.tandfonline.com/doi/10.1080/19420862.2022.2083467Α-hemolysinleukocidinepitope mappinghydrogen/deuterium exchange mass spectrometrypneumoniaStaphylococcus aureus |
| spellingShingle | Shweta Kailasan Ravi Kant Madeleine Noonan-Shueh Tulasikumari Kanipakala Grant Liao Sergey Shulenin Daisy W. Leung Richard A. Alm Rajan P. Adhikari Gaya K. Amarasinghe Michael L. Gross M. Javad Aman Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization mAbs Α-hemolysin leukocidin epitope mapping hydrogen/deuterium exchange mass spectrometry pneumonia Staphylococcus aureus |
| title | Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization |
| title_full | Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization |
| title_fullStr | Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization |
| title_full_unstemmed | Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization |
| title_short | Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization |
| title_sort | antigenic landscapes on staphylococcus aureus pore forming toxins reveal insights into specificity and cross neutralization |
| topic | Α-hemolysin leukocidin epitope mapping hydrogen/deuterium exchange mass spectrometry pneumonia Staphylococcus aureus |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2022.2083467 |
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