Bieri, jan (2022). Receptor switching controls human parvovirus B19 tropism and cell entry. (Thesis). Universität Bern, Bern
|
Text
22bieri_j.pdf - Thesis Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND 4.0). Download (2MB) | Preview |
Abstract
Cellular receptors are essential for virus entry and spread. Their identification is fundamental to understand the tropism and pathogenesis of the infection. Parvovirus B19 (B19V) is a human pathogen with global prevalence and has a marked tropism for erythroid progenitor cells (EPCs) in the bone marrow. Globoside, a highly abundant membrane glycosphingolipid (GSL), is required for the infection and has been historically considered the primary receptor of the virus. However, the pathogenicity and narrow erythroid tropism of B19V do not correlate with the wide expression profile of globoside. Another receptor that is exclusively expressed in EPCs, here named VP1uR, was recently shown to be required and sufficient for virus entry. While VP1uR is the receptor required for entry and infection in EPCs, the role of globoside is not yet clear. To clarify the function of globoside in B19V infection, we knocked out the gene B3GalNT1 coding for the enzyme globoside synthase in UT7/Epo cells. The loss of this enzyme leads to the elimination of globoside and downstream GSLs. The B3GalNT1 KO cell line was used to investigate the contribution of globoside to virus entry. We confirmed that globoside does not have the expected function as the primary receptor required for B19V entry into permissive cells, a function that corresponds to VP1uR. Instead, we found that globoside has an essential role at a postentry step by facilitating the escape of the incoming viruses from the acidic endosomal vesicles. We also uncovered that the interaction of B19V with globoside occurs exclusively at mildly acidic pH values, similar to those encountered in early endosomes. In an artificially induced acidic environment, the virus interacts with globoside on the surface of UT7/Epo cells which enables internalization. The finding that B19V affinity for globoside is tightly controlled by the pH has major consequences in the overall virus infection. Under neutral conditions, which are characteristic of the extracellular milieu, B19V does not interact with the ubiquitously expressed globoside. This strategy prevents the redirection of the virus to nonpermissive tissues facilitating the selective targeting of the EPCs in the bone marrow. However, considering the broad expression profile of globoside, naturally occurring acidic niches in the body, such as the nasal mucosal surface, become potential targets for the virus, which may facilitate entry through the respiratory route. Taken together, pH-dependent receptor switching between the widely expressed GSL globoside and the restricted VP1uR represents an evolutionary adaptation controlling the erythroid tropism of B19V.
| Item Type: | Thesis |
|---|---|
| Dissertation Type: | Cumulative |
| Date of Defense: | 7 April 2022 |
| Subjects: | 500 Science > 540 Chemistry 500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
| Institute / Center: | 08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
| Depositing User: | Hammer Igor |
| Date Deposited: | 18 Jun 2024 10:19 |
| Last Modified: | 19 Jun 2024 02:08 |
| URI: | https://boristheses.unibe.ch/id/eprint/5142 |
Actions (login required)
 |
View Item |