Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization
Influenza virus alters glycosylation patterns on its surface exposed glycoproteins to evade host adaptive immune responses. The viral hemagglutinin (HA), in particular the H3 subtype, has increased its overall surface glycosylation since its introduction in 1968. We previously showed that modulating...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.737973/full |
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| author | Dana N. Thornlow Dana N. Thornlow Andrew N. Macintyre Thomas H. Oguin Amelia B. Karlsson Erica L. Stover Heather E. Lynch Gregory D. Sempowski Gregory D. Sempowski Aaron G. Schmidt Aaron G. Schmidt |
| author_facet | Dana N. Thornlow Dana N. Thornlow Andrew N. Macintyre Thomas H. Oguin Amelia B. Karlsson Erica L. Stover Heather E. Lynch Gregory D. Sempowski Gregory D. Sempowski Aaron G. Schmidt Aaron G. Schmidt |
| author_sort | Dana N. Thornlow |
| collection | DOAJ |
| description | Influenza virus alters glycosylation patterns on its surface exposed glycoproteins to evade host adaptive immune responses. The viral hemagglutinin (HA), in particular the H3 subtype, has increased its overall surface glycosylation since its introduction in 1968. We previously showed that modulating predicted N-linked glycosylation sites on H3 A/Hong Kong/1/1968 HA identified a conserved epitope at the HA interface. This epitope is occluded on the native HA trimer but is likely exposed during HA “breathing” on the virion surface. Antibodies directed to this site are protective via an ADCC-mediated mechanism. This glycan engineering strategy made an otherwise subdominant epitope dominant in the murine model. Here, we asked whether cysteine stabilization of the hyperglycosylated HA trimer could reverse this immunodominance by preventing access to the interface epitope and focus responses to the HA receptor binding site (RBS). While analysis of serum responses from immunized mice did not show a redirection to the RBS, cysteine stabilization did result in an overall reduction in immunogenicity of the interface epitope. Thus, glycan engineering and cysteine stabilization are two strategies that can be used together to alter immunodominance patterns to HA. These results add to rational immunogen design approaches used to manipulate immune responses for the development of next-generation influenza vaccines. |
| first_indexed | 2024-12-14T09:21:58Z |
| format | Article |
| id | doaj.art-1d4b5aa96ea545c7a412bb252d295dee |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T09:21:58Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1d4b5aa96ea545c7a412bb252d295dee2022-12-21T23:08:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.737973737973Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide StabilizationDana N. Thornlow0Dana N. Thornlow1Andrew N. Macintyre2Thomas H. Oguin3Amelia B. Karlsson4Erica L. Stover5Heather E. Lynch6Gregory D. Sempowski7Gregory D. Sempowski8Aaron G. Schmidt9Aaron G. Schmidt10Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United StatesDepartment of Microbiology, Harvard Medical School, Boston, MA, United StatesDuke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesDuke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesDuke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesDuke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesDuke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesDuke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesDepartments of Medicine and Pathology, Duke University School of Medicine, Durham, NC, United StatesRagon Institute of MGH, MIT and Harvard, Cambridge, MA, United StatesDepartment of Microbiology, Harvard Medical School, Boston, MA, United StatesInfluenza virus alters glycosylation patterns on its surface exposed glycoproteins to evade host adaptive immune responses. The viral hemagglutinin (HA), in particular the H3 subtype, has increased its overall surface glycosylation since its introduction in 1968. We previously showed that modulating predicted N-linked glycosylation sites on H3 A/Hong Kong/1/1968 HA identified a conserved epitope at the HA interface. This epitope is occluded on the native HA trimer but is likely exposed during HA “breathing” on the virion surface. Antibodies directed to this site are protective via an ADCC-mediated mechanism. This glycan engineering strategy made an otherwise subdominant epitope dominant in the murine model. Here, we asked whether cysteine stabilization of the hyperglycosylated HA trimer could reverse this immunodominance by preventing access to the interface epitope and focus responses to the HA receptor binding site (RBS). While analysis of serum responses from immunized mice did not show a redirection to the RBS, cysteine stabilization did result in an overall reduction in immunogenicity of the interface epitope. Thus, glycan engineering and cysteine stabilization are two strategies that can be used together to alter immunodominance patterns to HA. These results add to rational immunogen design approaches used to manipulate immune responses for the development of next-generation influenza vaccines.https://www.frontiersin.org/articles/10.3389/fimmu.2021.737973/fullinfluenzahemagglutininglycansimmunogen designadaptive immunityB cells |
| spellingShingle | Dana N. Thornlow Dana N. Thornlow Andrew N. Macintyre Thomas H. Oguin Amelia B. Karlsson Erica L. Stover Heather E. Lynch Gregory D. Sempowski Gregory D. Sempowski Aaron G. Schmidt Aaron G. Schmidt Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization Frontiers in Immunology influenza hemagglutinin glycans immunogen design adaptive immunity B cells |
| title | Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization |
| title_full | Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization |
| title_fullStr | Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization |
| title_full_unstemmed | Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization |
| title_short | Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization |
| title_sort | altering the immunogenicity of hemagglutinin immunogens by hyperglycosylation and disulfide stabilization |
| topic | influenza hemagglutinin glycans immunogen design adaptive immunity B cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.737973/full |
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