Multi-Parameter Phenotype-Based Investigations of Attenuation in Herpes Simplex Virus
Restricted (Penn State Only)
- Author:
- Dweikat, Sarah
- Graduate Program:
- Molecular, Cellular, and Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 10, 2024
- Committee Members:
- Melissa Rolls, Program Head/Chair
David Kennedy, Major Field Member
Moriah Szpara, Chair & Dissertation Advisor
Lisa Akhtar, Special Member
Ilias Georgakopoulos-Soares, Outside Unit Member
Troy Sutton, Outside Field Member - Keywords:
- hsv
neonatal
genomics
phenotypic diversity
minor variants - Abstract:
- Herpes simplex virus 1 (HSV1) infects approximately 3.7 billion people worldwide with persistent symptoms that range from mild oral or genital lesions to severe encephalitis. Most new viral infections occur in children or young adults, but neonates can also be infected during childbirth or shortly after. Neonatal infections cause a much higher frequency of severe outcomes including death. Variation in disease outcomes can be attributed to both host responses, where deficiencies in host immunity can impact viral disease outcome, and to viral diversity, ranging from highly virulent to attenuated strains. With the evolution of HSV1 in human populations, the virus has accumulated broad genetic diversity, complicating the association of individual genetic features with phenotype. In this thesis, I explored the viral genetic contributors to disease severity in both neonates and adults by assessing HSV1 phenotypic and genetic characteristics to define attributes of viral attenuation. Incorporation of clinical HSV1 samples was valuable for identifying new contributors to virulence not previously characterized. These studies showed that the integration of both in vitro and in vivo assays facilitated viral classification. At least a portion of attenuated strains tended to cluster based on their genetic distance, and this clustering behavior could be seen with both neonatal and mouse infection data. Virulent and attenuated strains contained distinguishing genetic markers that allowed classification based on multivariate models. The methodology presented in this thesis provides a framework for prediction of disease outcome in clinical neonatal infections.