Functional and Structural Studies of Respiratory Syncytial Virus Fusion (RSV F) Protein and Neutralizing Antibody
| dc.contributor.advisor | Ma, Jianpeng | en_US |
| dc.creator | Xie, Qingqing | en_US |
| dc.date.accessioned | 2019-05-17T15:17:18Z | en_US |
| dc.date.available | 2019-05-17T15:17:18Z | en_US |
| dc.date.created | 2018-05 | en_US |
| dc.date.issued | 2018-04-18 | en_US |
| dc.date.submitted | May 2018 | en_US |
| dc.date.updated | 2019-05-17T15:17:18Z | en_US |
| dc.description.abstract | Human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in newborns, young children, and the elderly; causing significant morbidity and mortality each year. Unfortunately, there is currently no licensed vaccine for prophylaxis of RSV infection, and the therapeutic options are limited. The research and development of efficient RSV vaccine or therapeutic antibody has been a priority globally. RSV fusion (F) glycoprotein on the surface of the particle plays a central role in infection, mediating viral entry into host. It is an almost exclusive target for vaccine design and therapeutic antibody development in this field. RSV F has multiple antigenic sites on the pre-fusion and the post-fusion conformations. In Chapter 2, we characterized a series of monoclonal antibodies. We found a novel one, designated as R4.C6, binds with sub-nanomole affinity to a unique neutralizing site that occupies an intermediate position between antigenic sites II and IV on the globular head. Cryo-EM and 3D image reconstruction at 3.9 Å resolution was used to reveal the interaction of R4.C6 Fab in complex with the RSV F glycoprotein. Three R4.C6 Fab were found to bind to a quaternary epitope across two protomers; both heavy chain and light chain have interactions with site II of one protomer and site IV of the neighboring protomer. These results further our understanding of the antigenic complexity of the F protein and provide new insight into the design of RSV vaccines. The F glycoprotein is structurally complex with multiple conformations. It undergoes conformation shift from prefusion to pre-hairpin intermediate and finally to postfusion state. The combined energies released during multiple conformational rearrangements are used to bring the N- and C-terminal of RSV F1 subunit together, forcing the close contacts of virus and host cell membranes, and finally membrane fusion. In Chapter 3, we performed single particle cryo-EM analysis for another form of RSV F, named as BV2052. The 5 Å resolution density map shows some features that distinguished from the prefusion and postfusion state. BV2052 is in a intermediate state. This helps us understand the fusion mechanism. | en_US |
| dc.format.mimetype | application/pdf | en_US |
| dc.identifier.citation | Xie, Qingqing. "Functional and Structural Studies of Respiratory Syncytial Virus Fusion (RSV F) Protein and Neutralizing Antibody." (2018) Diss., Rice University. <a href="https://hdl.handle.net/1911/105762">https://hdl.handle.net/1911/105762</a>. | en_US |
| dc.identifier.uri | https://hdl.handle.net/1911/105762 | en_US |
| dc.language.iso | eng | en_US |
| dc.rights | Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder. | en_US |
| dc.subject | Respiratory syncytial virus | en_US |
| dc.subject | Fusion Protein | en_US |
| dc.subject | Monoclonal antibody | en_US |
| dc.subject | Antigenic site | en_US |
| dc.subject | Intermediate state | en_US |
| dc.subject | Single particle Cryo-EM | en_US |
| dc.title | Functional and Structural Studies of Respiratory Syncytial Virus Fusion (RSV F) Protein and Neutralizing Antibody | en_US |
| dc.type | Thesis | en_US |
| dc.type.material | Text | en_US |
| thesis.degree.department | Bioengineering | en_US |
| thesis.degree.discipline | Engineering | en_US |
| thesis.degree.grantor | Rice University | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy | en_US |
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