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Evaluation of a prophylactic L2-based vaccine in the pre-clinical model Mastomys coucha and establishment of an in vitro infection model for the cutaneous papillomavirus MnPV

Cao, Rui

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Abstract

Non-melanoma skin cancer (NMSC) is the most frequent cancer in the Caucasian population. Infections with cutaneous human papillomaviruses (HPVs) in conjunction with UV and immunosuppression are risk factors in the development of this type of cancer. As known by in silico analyses, an epitope within the N-terminus of the HPV minor capsid protein L2 is highly conserved across numerous HPV types and theoretically should elicit a pan cross-neutralizing response. To study this subject in a preclinical system, a MnPV L2-based vaccine was developed and evaluated in Mastomys coucha, a rodent naturally and persistently infected with MnPV. Vaccination with MnPV L2 or VLPs can induce a strong humoral immune response against L2 or VLPs. Moreover, UV irradiation did not influence antibody reactivity to MnPV L2 or VLPs. However, L2-specific antibodies were not persisting as long as the antibody response induced after VLP vaccination. Furthermore, there was no significant difference in the appearance of skin tumors among unvaccinated and vaccinated animals suggesting that an L2-based vaccine only should be considered with caution. Additionally, in order to gain a deeper insight into cutaneous papillomaviruses and UV in the development of skin cancer, a short-term in vitro infection system was established. Transcripts from both the early (E6, E7 and E1^E4) and the late (E1^E4, L1) promoter as well as the viral early protein E4 and E7 were detectable in infected keratinocytes, supporting the investigation of the MnPV/host cell interplay. Moreover, the infected keratinocytes were committed to differentiation via increased cell-to-cell contact, differentiation inducers and UV exposure, leading to an increase of L1 mRNA. This indicates that UV-induced differentiation might influence the productive MnPV life cycle.

Taken together, the current study provides a basis for the development of L2-based vaccines against cutaneous papillomavirus infection especially together with frequent sun exposure and further research on the cutaneous papillomavirus- and UV-driven skin tumorigenesis.

Document type: Dissertation
Supervisor: Müller, Prof. Dr. Martin
Place of Publication: Heidelberg
Date of thesis defense: 21 October 2020
Date Deposited: 12 Nov 2020 11:24
Date: 2021
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
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