Het effect van glycosylatie en antilichaam-geïnduceerde internalisatie van het respiratoir syncytieel virus fusieproteïne op de inductie en activiteit van antilichamen

Datum: 16 maart 2018

Locatie: Auditorium O1 (UAntwerpen, Campus Drie Eiken, gebouw O) - Universiteitsplein 1 - 2610 Wilrijk (Antwerpen) (route: UAntwerpen, Campus Drie Eiken)

Tijdstip: 16 - 18 uur

Promovendus: Annelies Leemans

Promotor: Peter Delputte, Paul Cos

Korte beschrijving: Doctoraatsverdediging Annelies Leemans - Departement Biomedische Wetenschappen

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRI) in infants worldwide and the primary cause of hospitalization during the first year of life. A complex interaction between the virus and the host response upon infection, which may lead to enhanced disease, hampers the development of vaccines, and currently  none are available. A key finding in RSV disease is that even natural infection provides limited protection against reinfection and that high levels of virus-neutralizing antibodies are not always able to prevent infection. As such, people are frequently reinfected throughout life. Although several types of vaccines are in development, induction of high levels of protective RSV-specific antibodies remains difficult. Clearly, RSV has developed mechanisms to interfere with the efficacy of antibody-mediated immunity. This thesis focused on two characteristics of the RSV fusion (F) protein which have been previously associated with the modulation of antibody-mediated immunity for other viruses.

Firstly, internalization of viral glycoproteins expressed on the cell surface of infected cells upon interaction with virus-specific antibodies was studied. This process was shown to occur in RSV-infected cells, both cell lines and cultures of primary bronchial epithelial cells. Because of this internalization, RSV F proteins were removed from the cell surface together with F-specific antibodies. It is expected that this will hamper antibody-mediated effector mechanisms, yet further research is needed to confirm this.

Secondly, N-glycosylation of the F protein was studied, since N-glycans may interfere with both the induction and activity of antibodies. Immunogenicity of the F protein glycan mutants was studied by analysis of antibody responses upon DNA immunization with wild type F and mutants in which single or multiple of each of the five conserved N-X-S/T sequons, that code for attachment of N-glycans, were removed. Immunization with F DNA with the glycosylation site N116 mutation elicited higher neutralizing antibody responses compared with wild type F, and this resulted in improved protection against infection. Glycomutant F proteins were also incorporated into RSV virus particles using an advanced RSV reverse genetics system. Individual mutants of each of the five conserved sites resulted in the recovery of replication-competent virus, though differences in replication efficiency were observed. Higher neutralizing antibody titers were detected for some glycomutants compared with wild type infection. Our data provides new insights in the effect of loss of F N-glycosylation sites on the immunogenicity of RSV F. Further research is ongoing to allow implementation of our findings in vaccine candidates which are currently in development.

Link: https://www.uantwerpen.be/nl/faculteiten/faculteit-fbd/onderzoek/doctoraatsverdedigen/