Many neurotropic viruses are transmitted trans-synaptically, including measles, polio, rabies and some herpesviruses. Nevertheless, the viral protein-neuronal protein interactions that govern this process are not known. Moreover, while these viruses cause rapid, highly productive infections in the periphery, most are associated with chronic infections in the brain, likely due to reduced viral progeny production and cytopathology in neurons. Thus, the objectives of this proposal are to define how viruses, such as measles virus, interact with neuronal proteins to affect both intra- and inter-neuronal transport, and to establish how this mode of spread is associated with chronic central nervous system infections. These broad objectives will be accomplished through completion of two Specific Aims. In the first aim, intra-neuronal spread of measles virus to the synapse is studied, which will characterize the viral proteins that are present at synaptic membranes, and whether these proteins are required for trans-synaptic spread. In addition, interaction with cellular motor proteins that govern movement along microtubules will be determined. In the second aim, inter-neuronal measles transmission is addressed, and the role of a putative, novel fusion protein receptor, neurokinin-1, ascertained. Specifically, we will establish if neurokinin-1 is required for viral neurotransmission, whether the measles fusion protein and neurokinin-1 interact, and, ultimately, how blockade of this proposed interaction affects viral spread and pathogenesis in a susceptible transgenic mouse model. Successful completion of these aims will contribute to our long-term goals that include: (1) identification of cellular factors that contribute to viral persistence in neurons;(2) determination of how viral persistence may lead to host impairment without neuronal loss;and eventually (3) development of treatments to prevent or reverse the life- threatening consequences of chronic CNS infections.

Public Health Relevance

Viral infections of the central nervous system (CNS) are often associated with chronic neurological diseases, rather than the acute illnesses these viruses cause in the periphery. In this application, we focus on measles virus neuropathogenesis using novel mouse models, primary neuronal cell cultures, and human neuronal cell lines. The broad, long-term objectives of this proposal are to define how measles virus particles interact with neuronal proteins to affect both intra- and inter- neuronal viral transport, and to determine how spread across the synapse may contribute to neuropathogenesis. Successful completion of the proposed aims will provide the foundation for the development of treatments to prevent or reverse the life-threatening consequences of chronic CNS infections caused by viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060701-02
Application #
7627984
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$381,719
Indirect Cost
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Miller, Katelyn D; Rall, Glenn F (2017) What Kaplan-Meier survival curves don't tell us about CNS disease. J Neuroimmunol 308:25-29
Cavanaugh, Sarah E; Holmgren, Alicia M; Rall, Glenn F (2015) Homeostatic interferon expression in neurons is sufficient for early control of viral infection. J Neuroimmunol 279:11-9
O'Donnell, Lauren A; Conway, Stephen; Rose, R Wesley et al. (2012) STAT1-independent control of a neurotropic measles virus challenge in primary neurons and infected mice. J Immunol 188:1915-23
Matullo, Christine M; O'Regan, Kevin J; Curtis, Mark et al. (2011) CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge. PLoS Pathog 7:e1002462
O'Donnell, Lauren A; Rall, Glenn F (2010) Blue moon neurovirology: the merits of studying rare CNS diseases of viral origin. J Neuroimmune Pharmacol 5:443-55
Matullo, Christine M; O'Regan, Kevin J; Hensley, Harvey et al. (2010) Lymphocytic choriomeningitis virus-induced mortality in mice is triggered by edema and brain herniation. J Virol 84:312-20
Young, V A; Rall, G F (2009) Making it to the synapse: measles virus spread in and among neurons. Curr Top Microbiol Immunol 330:3-30