Dissertation/Thesis Abstract

Functions of the Viral Attachment Protein in Reovirus Neurovirulence
by Sutherland, Danica Marie, Ph.D., Vanderbilt University, 2018, 121; 13877290
Abstract (Summary)

Viral invasion of the central nervous system (CNS) is a significant cause of morbidity and mortlity worldwide, particularly in young children (1). The nervous system presents a challenging site for viruses to access, with multiple physical and immunological barriers that limit pathogen invasion. To invade the CNS, viruses must access cell-surface receptors for binding and entry events. Virus-receptor interactions also govern tropism and often control disease type and severity. For many viruses, the identities of receptors and other cellular determinants of viral tropism remain elusive. Understanding where and how viral capsid components engage neural receptors and the effect of these interactions on tropism and disease may illuminate targets to prevent viral neuroinvasion.

Mammalian orthoreoviruses (reoviruses) provide a highly tractable and well-established system to identify mechanisms of viral entry into the CNS. Reoviruses are non-enveloped particles containing a 10-segmented, double-stranded (ds) RNA genome that replicate well in culture and can be altered via a robust reverse-genetics system (2, 3). While reovirus causes similar age-restricted disease in many young mammals (4-6), most studies employ newborn mice. Following peroral or intracranial inoculation of newborn mice, reovirus displays serotype-specific patterns of tropism in the brain and concomitant disease (Fig. I-1). Serotype 1 (T1) strains infect ependymal cells lining the ventricles of the brain and cause a non-lethal hydrocephalus (7). In contrast, serotype 3 (T3) strains infect specific neuron populations in the CNS and produce a fulminant, and often lethal, encephalitis (8). These differences in tropism and disease have been genetically mapped to the reovirus S1 gene using single-gene reassortant viruses (9). However, viral and host gene sequences that mediate either T1 or T3 tropism have not been defined.

In Chapter I of my dissertation, I introduce key themes about mechanisms of neuroinvasion and the disease consequences of CNS infection. I describe fundamental knowledge and open areas of research pertaining to reovirus infection in the CNS and expand on reovirus-receptor interactions. I conclude Chapter I with a summary of viral oncolytic therapies and highlight strengths and opportunities for improvement of reovirus oncolytics. In Chapter II, I describe the design and implementation of σ1- chimeric reoviruses to identify sequences in the S1 gene that dictate neurotropism and virulence in the CNS. In these studies, I found that homologous sequences at the viriondistal end of the viral attachment protein are responsible for neuron and ependymal cell targeting. In Chapter III, I identify sequences of the NgR1 reovirus receptor that are required for binding and post-binding functions and elucidate the viral ligand for NgR1, which is the σ3 outer-capsid protein, using a combination of genetic, biochemical, and structural approaches. Finally, in Chapter IV, I review conclusions from results presented in Chapters II and III, examine new questions raised by these studies, and discuss future directions of this work. Collectively, my dissertation research has unveiled viral and host sequences that contribute to neural cell targeting and will improve strategies and knowledge to design targeted oncolytic therapies.

Indexing (document details)
Advisor: Dermody, Terence
Commitee: Carter, Bruce, Chappell, Tim, Dermody, Terence, Lacy, Borden, Ruley, Earl
School: Vanderbilt University
Department: Microbiology and Immunology
School Location: United States -- Tennessee
Source: DAI-B 80/08(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Microbiology, Virology, Immunology
Keywords: Central nervous system, Encephalitis, Hydrocephalus, Receptor, Virus
Publication Number: 13877290
ISBN: 9781392060636
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