A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesResearch in context
Summary: Background: Worldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis. Methods: Here, we u...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239642300004X |
| _version_ | 1811167312511762432 |
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| author | Stéphanie Pons Eric Frapy Youssouf Sereme Charlotte Gaultier François Lebreton Andrea Kropec Olga Danilchanka Laura Schlemmer Cécile Schrimpf Margaux Allain François Angoulvant Hervé Lecuyer Stéphane Bonacorsi Hugues Aschard Harry Sokol Colette Cywes-Bentley John J. Mekalanos Thomas Guillard Gerald B. Pier Damien Roux David Skurnik |
| author_facet | Stéphanie Pons Eric Frapy Youssouf Sereme Charlotte Gaultier François Lebreton Andrea Kropec Olga Danilchanka Laura Schlemmer Cécile Schrimpf Margaux Allain François Angoulvant Hervé Lecuyer Stéphane Bonacorsi Hugues Aschard Harry Sokol Colette Cywes-Bentley John J. Mekalanos Thomas Guillard Gerald B. Pier Damien Roux David Skurnik |
| author_sort | Stéphanie Pons |
| collection | DOAJ |
| description | Summary: Background: Worldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis. Methods: Here, we used Transposon Sequencing of saturated banks of mutants (TnSeq) to evaluate E. coli K1 genetic fitness in murine neonatal meningitis. We identified E. coli K1 genes encoding for factors important for systemic dissemination and brain infection, and focused on products with a likely outer-membrane or extra-cellular localization, as these are potential vaccine candidates. We used in vitro and in vivo models to study the efficacy of active and passive immunization. Results: We selected for further study the conserved surface polysaccharide Poly-β-(1-6)-N-Acetyl Glucosamine (PNAG), as a strong candidate for vaccine development. We found that PNAG was a virulence factor in our animal model. We showed that both passive and active immunization successfully prevented and/or treated meningitis caused by E. coli K1 in neonatal mice. We found an excellent opsonophagocytic killing activity of the antibodies to PNAG and in vitro these antibodies were also able to decrease binding, invasion and crossing of E. coli K1 through two blood brain barrier cell lines. Finally, to reinforce the potential of PNAG as a vaccine candidate in bacterial neonatal meningitis, we demonstrated that Group B Streptococcus, the main cause of neonatal meningitis in developed countries, also produced PNAG and that antibodies to PNAG could protect in vitro and in vivo against this major neonatal pathogen. Interpretation: Altogether, these results indicate the utility of a high-throughput DNA sequencing method to identify potential immunotherapy targets for a pathogen, including in this study a potential broad-spectrum target for prevention of neonatal bacterial infections. Fundings: ANR Seq-N-Vaq, Charles Hood Foundation, Hearst Foundation, and Groupe Pasteur Mutualité. |
| first_indexed | 2024-04-10T16:07:02Z |
| format | Article |
| id | doaj.art-6072e4ffadcf4741b891307baa3891fb |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-10T16:07:02Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-6072e4ffadcf4741b891307baa3891fb2023-02-10T04:22:25ZengElsevierEBioMedicine2352-39642023-02-0188104439A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesResearch in contextStéphanie Pons0Eric Frapy1Youssouf Sereme2Charlotte Gaultier3François Lebreton4Andrea Kropec5Olga Danilchanka6Laura Schlemmer7Cécile Schrimpf8Margaux Allain9François Angoulvant10Hervé Lecuyer11Stéphane Bonacorsi12Hugues Aschard13Harry Sokol14Colette Cywes-Bentley15John J. Mekalanos16Thomas Guillard17Gerald B. Pier18Damien Roux19David Skurnik20Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Anesthesiology and Critical Care, Sorbonne University, GRC 29, AP-HP, DMU DREAM, Pitié-Salpêtrière, Paris, FranceCNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, France; Faculté de Médecine, University of Paris City, Paris, FranceCNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, France; Faculté de Médecine, University of Paris City, Paris, FranceDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Ophthalmology and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02114, USADivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Microbiology, Harvard Medical School, Boston, MA 02115, USACNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, FranceCNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, FranceCNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, FranceAssistance Publique - Hôpitaux de Paris, Pediatric Emergency Department, Necker-Enfants Malades University Hospital, University of Paris City, Paris, France; INSERM, Centre de Recherche des Cordeliers, UMRS 1138, Sorbonne Université, Université de Paris, Paris, FranceCNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, France; Faculté de Médecine, University of Paris City, Paris, France; Department of Clinical Microbiology, Fédération Hospitalo-Universitaire Prématurité (FHU PREMA), Necker-Enfants Malades University Hospital, University of Paris City, Paris, FranceE IAME, UMR 1137, INSERM, Université de Paris, AP-HP, Paris, France; Laboratoire de Microbiologie, Hôpital Robert Debré, AP-HP, Paris, FranceCentre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USAGastroenterology Department, Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, F-75012 Paris, France; INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France; Paris Centre for Microbiome Medicine FHU, Paris, FranceDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Microbiology, Harvard Medical School, Boston, MA 02115, USADivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Université de Reims Champagne-Ardenne, SFR CAP-Santé, Inserm UMR-S 1250 P3Cell, Reims, France; Laboratoire de Bactériologie-Virologie-Hygiène Hospitalière-Parasitologie-Mycologie, CHU, Reims, FranceDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Université de Paris, INSERM, UMR 1137 IAME, F-75018 Paris, France; AP-HP, Médecine Intensive Réanimation, Hôpital Louis Mourier, F-92700 Colombes, FranceDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; CNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, France; Faculté de Médecine, University of Paris City, Paris, France; Department of Clinical Microbiology, Fédération Hospitalo-Universitaire Prématurité (FHU PREMA), Necker-Enfants Malades University Hospital, University of Paris City, Paris, France; Corresponding author. Département de Microbiologie, Université de Paris- Hôpital Necker Enfants Malades, 149, rue de Sèvres, 75015 Paris, France.Summary: Background: Worldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis. Methods: Here, we used Transposon Sequencing of saturated banks of mutants (TnSeq) to evaluate E. coli K1 genetic fitness in murine neonatal meningitis. We identified E. coli K1 genes encoding for factors important for systemic dissemination and brain infection, and focused on products with a likely outer-membrane or extra-cellular localization, as these are potential vaccine candidates. We used in vitro and in vivo models to study the efficacy of active and passive immunization. Results: We selected for further study the conserved surface polysaccharide Poly-β-(1-6)-N-Acetyl Glucosamine (PNAG), as a strong candidate for vaccine development. We found that PNAG was a virulence factor in our animal model. We showed that both passive and active immunization successfully prevented and/or treated meningitis caused by E. coli K1 in neonatal mice. We found an excellent opsonophagocytic killing activity of the antibodies to PNAG and in vitro these antibodies were also able to decrease binding, invasion and crossing of E. coli K1 through two blood brain barrier cell lines. Finally, to reinforce the potential of PNAG as a vaccine candidate in bacterial neonatal meningitis, we demonstrated that Group B Streptococcus, the main cause of neonatal meningitis in developed countries, also produced PNAG and that antibodies to PNAG could protect in vitro and in vivo against this major neonatal pathogen. Interpretation: Altogether, these results indicate the utility of a high-throughput DNA sequencing method to identify potential immunotherapy targets for a pathogen, including in this study a potential broad-spectrum target for prevention of neonatal bacterial infections. Fundings: ANR Seq-N-Vaq, Charles Hood Foundation, Hearst Foundation, and Groupe Pasteur Mutualité.http://www.sciencedirect.com/science/article/pii/S235239642300004XNeonatal meningitisVaccineHigh-throughput sequencingE. coli K1PNAG |
| spellingShingle | Stéphanie Pons Eric Frapy Youssouf Sereme Charlotte Gaultier François Lebreton Andrea Kropec Olga Danilchanka Laura Schlemmer Cécile Schrimpf Margaux Allain François Angoulvant Hervé Lecuyer Stéphane Bonacorsi Hugues Aschard Harry Sokol Colette Cywes-Bentley John J. Mekalanos Thomas Guillard Gerald B. Pier Damien Roux David Skurnik A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesResearch in context EBioMedicine Neonatal meningitis Vaccine High-throughput sequencing E. coli K1 PNAG |
| title | A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesResearch in context |
| title_full | A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesResearch in context |
| title_fullStr | A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesResearch in context |
| title_full_unstemmed | A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesResearch in context |
| title_short | A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesResearch in context |
| title_sort | high throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonatesresearch in context |
| topic | Neonatal meningitis Vaccine High-throughput sequencing E. coli K1 PNAG |
| url | http://www.sciencedirect.com/science/article/pii/S235239642300004X |
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