Actions for The Role of Polyomavirus Capsid Mutations in Antibody Evasion and Virulence
The Role of Polyomavirus Capsid Mutations in Antibody Evasion and Virulence
- Author
- Lauver, Matthew
- Published
- [University Park, Pennsylvania] : Pennsylvania State University, 2022.
- Physical Description
- 1 electronic document
- Additional Creators
- Buchkovich, Nicholas
Access Online
- etda.libraries.psu.edu , Connect to this object online.
- Graduate Program
- Restrictions on Access
- Restricted (PSU Only).
- Summary
- Polyomaviruses (PyV) are small, DNA viruses that infect a wide range of animal species. In healthy individuals, a balance between PyV replication and the host's immune system results in a life-long, asymptomatic infection, typically within the urinary tract. Conditions of immune suppression, however, can upset this balance and lead to severe PyV-mediated disease. JCPyV is a human PyV that infects more than 50% of the adult population and is the causative agent of progressive multifocal leukoencephalopathy (PML), a frequently fatal demyelinating brain disease. Various forms of immune suppression impacting T cells, including HIV/AIDS, hematological malignancies, and immunomodulatory therapies, are associated with the development of PML. However, the steps leading from JCPyV persistence in the kidney to infection of the brain and PML development are poorly understood. This presents a major limitation to identifying at-risk patients and detecting PML prior to the development of severe disease. A hallmark of PML pathogenesis is the emergence of variant JCPyVs that carry mutations in the major capsid protein, VP1. These mutations are only found in PML patients, but their functions remain unknown. The overall aim of this dissertation is to understand the functions of these mutations and factors that contribute to their emergence using infection with mouse (Mu)PyV as a model of JCPyV infection and pathogenesis. To do this, we first examined the effects of the most common VP1 mutation seen in PML by generating a MuPyV variant carrying this mutation. We found that this mutant virus lost its ability to replicate in the kidney, as demonstrated by decreased infection in immune-competent and -compromised hosts, but retained the ability to replicate in the brain and cause neuropathology. Additionally, this mutant virus was highly resistant to a neutralizing antibody, which cryo EM reconstructions revealed to be result of the mutation blocking antibody attachment. Together, these findings implicate this mutation in both altering viral tropism and mediating antibody escape. Next, we investigated the relationship between T cell loss and VP1 mutations. PML occurs in the context of T cell immunosuppression, however the connection between T cell impairment and the emergence of VP1 mutant viruses remains unknown. We found that T cell loss in mice susceptible to antibody escape resulted in increased viral replication and the emergence of viruses with antibody escape mutations in VP1. Furthermore, T cell loss resulted in an inability to control infection when mice were challenged with an antibody escape mutant. We also identified viruses that developed multiple VP1 mutations, leading to enhanced neurovirulence and brain pathology. These data indicate that T cell deficiency enables the emergence and outgrowth of viral antibody escape mutants, including variants with neurovirulent potential. Finally, we examined the effect of two immunomodulatory therapies associated with PML and found that they impaired the MuPyV-specific T cell response and rendered mice susceptible to the emergence of antibody escape mutant viruses. Together, these studies provide a mechanism for the early stages of PML development - T cell suppression enabling the emergence of antibody escape mutant viruses that spread from the kidney to the brain and cause disease.
- Other Subject(s)
- Genre(s)
- Dissertation Note
- Ph.D. Pennsylvania State University 2022.
- Technical Details
- The full text of the dissertation is available as an Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
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