Voss, F. (Féline) (2017) The Inhibitory Role of Human a-defensin 5 in HPV16 Uptake and Infection. thesis, Medicine.
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Abstract
Human papillomavirus (HPV) is the number one sexually transmitted virus worldwide, of which high-risk HPV type 16 (HPV16) is causally associated with 50% of all cervical cancers and 90% of HPV-positive oropharyngeal cancers. Defensins are small peptides of the innate immune system that are expressed by epithelial cells in the genitourinary tract. Human adefensin 5 (HD5) has been shown to inhibit HPV16 infection. However, the mechanisms proposed by different studies are conflicting. Therefore, we have aimed to delineate the role of defensins in HPV16 uptake, infection, and its mucosal immune responses. Our study shows that HPV16 infection is blocked to near 100% when pretreating HPV16 PsV with HD5, indicating that HD5 does not require direct surface interaction with cellular receptors to block infection. Uptake assays give evidence that HD5 pretreated HPV16 are internalized by the cell, but are unable to reach the nucleus. In fact, a build-up of virus particles within acidic environments of the cell was observed, suggesting viral trafficking was halted at late endosomes or possibly lysosomes. From this data we conclude that HD5 interacts directly with the viral capsid, resulting in a build-up of virus particles in late endosomes and prevention of viral trafficking to the nucleus that completes infection. Throughout the investigation we have continuously refined our hypothesis for the mechanism by which HD5 blocks HPV16 infection. As viral uncoating is required for the HPV16 to escape the late endosomes, we currently hypothesize that HD5 inhibits this viral capsid dissociation by stabilizing the viral capsid.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Supervisor Rijksuniversiteit Groningen Nijman, Prof.dr. H.W. |
| Supervisor name: | Supervisor University of Southern California Kast, Prof.dr. and Daily supervisor and Skeate, Joey PhD candidate |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 11:00 |
| Last Modified: | 25 Jun 2020 11:00 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/2068 |
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