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Neuronal interferon signaling : implications for HSV-1 replication and pathogenesis / by Pamela Rosato

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Author	Rosato, Pamela, Pamela C.
Title	Neuronal interferon signaling : implications for HSV-1 replication and pathogenesis / by Pamela Rosato
Date	2014
Abstract	Herpes simplex virus-1 (HSV-1) establishes lifelong latent infections in the sensory neurons of the trigeminal ganglia (TG) wherein it retains the capacity to reactivate. The interferon (IFN)-driven antiviral response is critical for the control of HSV-1 infection. We therefore sought to further investigate this response in TG neurons using both in vitro and in vivo models. Utilizing cultured TG neurons from adult mice deficient in a variety of IFN signaling components, we show that HSV-1 replication was comparable in wild-type (WT) and IFN signaling-deficient neurons. Unexpectedly, a similar pattern was observed for the IFN-sensitive vesicular stomatitis virus (VSV). Despite these findings, TG neurons responded to IFN? treatment with STAT1 nuclear localization and restricted replication of both VSV and an HSV-1 strain deficient in ?34.5, while wild-type HSV-1 replication was largely unaffected. We further characterize this response in compartmentalized chamber cultures, which allow for the separation of axon and neuronal cell body (soma). We show that upon axonal infection, both soma and axonal IFN? signaling can reduce viral titers. While still under investigation, the mechanism of axonal IFN? signaling is through mechanisms independent of antiviral signaling at the soma and may also be independent of axonal trafficking. Taken together, these data show that adult TG neurons can mount an effective antiviral response only if provided with an exogenous source of IFN ?, and HSV-1 combats this response through ?34.5. Furthering these studies, through corneal infection of a mouse with a neural specific deletion of Stat1, we demonstrate that neural IFN signaling is critical for restricting HSV replication and pathogenesis, in addition to restricting cell tropism in the TG and zosteriform spread to the periocular skin of the eye in the absence of ?34.5. Together, these results further our understanding of the antiviral response of neurons and demonstrate a critical role for neuronal IFN signaling in host survival. A graphical summary of these findings can be found in Figure 1-3.
Description	1 online resource (xii, 171 pages) : illustrations (some color)
Format	application/pdf
College	Geisel School of Medicine at Dartmouth -- Department of Microbiology and Immunology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1921

Title	Page 1
Full Text	NEURONAL INTERFERON SIGNALING: IMPLICATIONS FOR HSV-1 REPLICATION AND PATHOGENESIS A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Microbiology and Immunology by Pamela Rosato DARTMOUTH COLLEGE Hanover, New Hampshire December, 2014

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