The overall goal of this project Is to understand the contribution of microtubules (MTs) to viral infectivity. MTs exist in dynamic and stabilized states. Upon stabilization, tubulin subunits comprising MTs become post- translationally modified (PTM). While both dynamic and stable MTs may play roles in viral infection, stable, PTM MTs may be particularly important. Viral proteins bind MT stabilizing factors, host cell factors critical for viral infectivity affect levels of stable MTs in cells and some viruses even enhance the formation of stable, PTM MTs in cell they infect. While we understand a number of the factors involved in MT stabilization pathways in cells, we have relatively little understanding of the relationship between viral infectivity and the functions that stable, PTM MTs provide during viral infection. In this project, we pursue three aims to enhance our understanding of the relationship between MT stability, tubulin PTMs and viral infectivity. We will conduct a screen for new factors involved in MT stability and viral infectivity by examining a family of MT interacting proteins implicated in MT stability. We will critically test the relationship between viral infectivity, tubulin PTMs, and MT stability, by developing strategies to generate cells lacking or overexpressing the two PTMs of tubulin that commonly occur in stable MTs of cells infected by viruses. And, we will examine the spatial relationships between viruses and different classes of MTs by developing new methods to image stable and PTM MTs in living ceils infected with fluorescent viruses and by testing the motility of viral motors on PTM MTs.
These aims will be conducted in collaboration with the Goff, Naghavi, Walsh and Vallee groups. The results of these studies will provide new mechanistic information into how different classes of MTs contribute to viral infection and will provide new insights into how viruses manipulate and take advantage of host cell factors to augment their infection. These studies will also identify new host cell factors that influence viral infection and hence have important implications forthe development of anti-viral and viral- based gene targeting strategies.

Public Health Relevance

Viruses use host cell microtubules to facilitate their infection, yet how they do so is unclear. In this proposal we develope new tools to explore the relationship between viral infectivity and specific types of microtubules that are stabilized and post-translationally modified. This work will shed new light on the role of microtubules in viral infection and identify new viral host cell factors with implications for viral therapies and for further understanding of the basic cellular factors regulating microtubule dynamcis and functions in cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
1P01GM105536-01A1
Application #
8667734
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
Rosenfeld, Amy B; Doobin, David J; Warren, Audrey L et al. (2017) Replication of early and recent Zika virus isolates throughout mouse brain development. Proc Natl Acad Sci U S A 114:12273-12278
Naghavi, Mojgan H; Walsh, Derek (2017) Microtubule Regulation and Function during Virus Infection. J Virol 91:
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Malikov, Viacheslav; da Silva, Eveline Santos; Jovasevic, Vladimir et al. (2015) HIV-1 capsids bind and exploit the kinesin-1 adaptor FEZ1 for inward movement to the nucleus. Nat Commun 6:6660
Scherer, Julian; Vallee, Richard B (2015) Conformational changes in the adenovirus hexon subunit responsible for regulating cytoplasmic dynein recruitment. J Virol 89:1013-23

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