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Authors: Tanneti, Shree Nikhila
Advisors: Enquist, Lynn W
Contributors: Molecular Biology Department
Keywords: alpha Herpesvirus
axonal sorting
neuronal maturation
neuronal spread
Pseudorabies Virus
Subjects: Virology
Molecular biology
Issue Date: 2020
Publisher: Princeton, NJ : Princeton University
Abstract: Alpha-herpesviruses establish a life-long infection in the nervous system of the affected host. While this infection is restricted to peripheral neurons in a heathy host, it can spread within the neuronal circuitry in compromised individuals leading to adverse health consequences. Human αherpesviruses include Herpes Simplex Virus types 1 and 2, that cause cold sores and lesions, and Varicella-Zoster Virus, the causative agent of chicken pox and shingles. Pseudorabies virus (PRV) is an αherpesvirus with exceptionally broad host range, infecting most mammals and rarely humans. For spread of infection between neurons, it requires the viral protein Us9 for sorting virus particles into axons by mediating an interaction of intracellular virus particles with neuronal transport machinery. Here we report that Us9-mediated axonal sorting also depends on the state of neuronal maturation, a process characterized with the polarization of dendrites, axons, and proteome composition changes. Immature superior cervical ganglia (SCGs) are part of the peripheral nervous system and have rudimentary neurites that lack protein markers of mature dendrites or axons. Immature SCGs can be infected by PRV, but unlike mature SCGs show markedly reduced Us9-dependent sorting of virus particles into neurites. Mature SCGs abundantly express a variety of proteins characteristic of membrane vesicle-transport machinery. Proteomics studies of infected mature neurons identified several novel Us9-associated virus and neuronal proteins with potential roles in the regulation of axonal sorting and subsequent anterograde spread of virus particles in axons. SMPD4/n-sMase3, a neuronal sphingomyelinase abundant in lipid-rafts that interacted with Us9, is found to inhibit the sorting of virus particles into axons and subsequent spread of infection. Such an interaction provides a novel potentially anti-viral host response. By contrast, we identified the viral protein Us2 as an inhibitor of Us9 independent virus spread. Several other Us9-associated proteins were identified and potential mechanisms that elucidate neuronal spread of alpha-herpesvirus infections are proposed.
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Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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