Anti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design
Abstract Enterotoxigenic Escherichia coli (ETEC) is estimated to cause approximately 380,000 deaths annually during sporadic or epidemic outbreaks worldwide. Development of vaccines against ETEC is very challenging due to the vast heterogeneity of the ETEC strains. An effective vaccines would have t...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/8c71423749de4016b747f5338a446935 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:8c71423749de4016b747f5338a446935 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:8c71423749de4016b747f5338a4469352021-12-02T10:44:09ZAnti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design10.1038/s41598-021-81895-02045-2322https://doaj.org/article/8c71423749de4016b747f5338a4469352021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81895-0https://doaj.org/toc/2045-2322Abstract Enterotoxigenic Escherichia coli (ETEC) is estimated to cause approximately 380,000 deaths annually during sporadic or epidemic outbreaks worldwide. Development of vaccines against ETEC is very challenging due to the vast heterogeneity of the ETEC strains. An effective vaccines would have to be multicomponent to provide coverage of over ten ETEC strains with genetic variabilities. There is currently no vaccine licensed to prevent ETEC. Nanobodies are successful new biologics in treating mucosal infectious disease as they recognize conserved epitopes on hypervariable pathogens. Cocktails consisting of multiple nanobodies could provide even broader epitope coverage at a lower cost compared to monoclonal antibodies. Identification of conserved epitopes by nanobodies can also assist reverse engineering of an effective vaccine against ETEC. By screening nanobodies from immunized llamas and a naïve yeast display library against adhesins of colonization factors, we identified single nanobodies that show cross-protective potency against eleven major pathogenic ETEC strains in vitro. Oral administration of nanobodies led to a significant reduction of bacterial colonization in animals. Moreover, nanobody-IgA fusion showed extended inhibitory activity in mouse colonization compared to commercial hyperimmune bovine colostrum product used for prevention of ETEC-induced diarrhea. Structural analysis revealed that nanobodies recognized a highly-conserved epitope within the putative receptor binding region of ETEC adhesins. Our findings support further rational design of a pan-ETEC vaccine to elicit robust immune responses targeting this conserved epitope.Alla AmcheslavskyAaron L. WallaceMonir EjemelQi LiConor T. McMahonMatteo StoppatoSerena GiuntiniZachary A. SchillerJessica R. PondishJacqueline R. ToomeyRyan M. SchneiderJordan MeisingerRaimond HeukersAndrew C. KruseEileen M. BarryBrian G. PierceMark S. KlempnerLisa A. CavaciniYang WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Alla Amcheslavsky Aaron L. Wallace Monir Ejemel Qi Li Conor T. McMahon Matteo Stoppato Serena Giuntini Zachary A. Schiller Jessica R. Pondish Jacqueline R. Toomey Ryan M. Schneider Jordan Meisinger Raimond Heukers Andrew C. Kruse Eileen M. Barry Brian G. Pierce Mark S. Klempner Lisa A. Cavacini Yang Wang Anti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design |
| description |
Abstract Enterotoxigenic Escherichia coli (ETEC) is estimated to cause approximately 380,000 deaths annually during sporadic or epidemic outbreaks worldwide. Development of vaccines against ETEC is very challenging due to the vast heterogeneity of the ETEC strains. An effective vaccines would have to be multicomponent to provide coverage of over ten ETEC strains with genetic variabilities. There is currently no vaccine licensed to prevent ETEC. Nanobodies are successful new biologics in treating mucosal infectious disease as they recognize conserved epitopes on hypervariable pathogens. Cocktails consisting of multiple nanobodies could provide even broader epitope coverage at a lower cost compared to monoclonal antibodies. Identification of conserved epitopes by nanobodies can also assist reverse engineering of an effective vaccine against ETEC. By screening nanobodies from immunized llamas and a naïve yeast display library against adhesins of colonization factors, we identified single nanobodies that show cross-protective potency against eleven major pathogenic ETEC strains in vitro. Oral administration of nanobodies led to a significant reduction of bacterial colonization in animals. Moreover, nanobody-IgA fusion showed extended inhibitory activity in mouse colonization compared to commercial hyperimmune bovine colostrum product used for prevention of ETEC-induced diarrhea. Structural analysis revealed that nanobodies recognized a highly-conserved epitope within the putative receptor binding region of ETEC adhesins. Our findings support further rational design of a pan-ETEC vaccine to elicit robust immune responses targeting this conserved epitope. |
| format |
article |
| author |
Alla Amcheslavsky Aaron L. Wallace Monir Ejemel Qi Li Conor T. McMahon Matteo Stoppato Serena Giuntini Zachary A. Schiller Jessica R. Pondish Jacqueline R. Toomey Ryan M. Schneider Jordan Meisinger Raimond Heukers Andrew C. Kruse Eileen M. Barry Brian G. Pierce Mark S. Klempner Lisa A. Cavacini Yang Wang |
| author_facet |
Alla Amcheslavsky Aaron L. Wallace Monir Ejemel Qi Li Conor T. McMahon Matteo Stoppato Serena Giuntini Zachary A. Schiller Jessica R. Pondish Jacqueline R. Toomey Ryan M. Schneider Jordan Meisinger Raimond Heukers Andrew C. Kruse Eileen M. Barry Brian G. Pierce Mark S. Klempner Lisa A. Cavacini Yang Wang |
| author_sort |
Alla Amcheslavsky |
| title |
Anti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design |
| title_short |
Anti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design |
| title_full |
Anti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design |
| title_fullStr |
Anti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design |
| title_full_unstemmed |
Anti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design |
| title_sort |
anti-cfae nanobodies provide broad cross-protection against major pathogenic enterotoxigenic escherichia coli strains, with implications for vaccine design |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/8c71423749de4016b747f5338a446935 |
| work_keys_str_mv |
AT allaamcheslavsky anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT aaronlwallace anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT monirejemel anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT qili anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT conortmcmahon anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT matteostoppato anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT serenagiuntini anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT zacharyaschiller anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT jessicarpondish anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT jacquelinertoomey anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT ryanmschneider anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT jordanmeisinger anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT raimondheukers anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT andrewckruse anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT eileenmbarry anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT briangpierce anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT marksklempner anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT lisaacavacini anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign AT yangwang anticfaenanobodiesprovidebroadcrossprotectionagainstmajorpathogenicenterotoxigenicescherichiacolistrainswithimplicationsforvaccinedesign |
| _version_ |
1718396840112553984 |