Abstract
This work focuses on the molecular mechanisms by which viruses
utilize host factors to spread from one cell to another. These
investigations focus the poxviruses vaccinia, variola, and
monkeypox. Vaccinia serves as the vaccine against variola, the
cause of smallpox. Following replication and maturation, Poxvirinae
virions travel to the cell surface along microtubules and fuse with
the plasma membrane to form cell-associated enveloped virions
(CEV). CEV can either form actin tails and move towards apposing
cells or detach to form extracellular enveloped virions (EEV). The
formation of actin tails is thought to mediate intra-tissue spread,
while EEV are thought to be important for intertissue
dissemination. The role of tyrosine kinases in actin motility and
release of EEV was investigated using cell lines lacking particular
kinases or with small molecules that inhibit kinase activity.
Experiments presented demonstrate that Src- and Abl-family tyrosine
kinases mediate actin motility, whereas release of infectious EEV
depends upon Abl-family tyrosine kinases. Moreover, the utilization
of these kinases by vaccinia, variola, and monkeypox is highly
conserved. One inhibitor, Gleevec, blocks Abl-family tyrosine
kinases and is FDA approved to treat patients with chronic
myelogenous leukemia. In mice, Gleevec reduces viral load of
vaccinia and protects from a lethal challenge whether administered
as a prophylactic or in a therapeutic context. Together, these
experiments support the role of EEV in dissemination and
pathogenesis of poxviruses in vivo. Moreover, these data suggest a
means to develop therapeutic strategies based on an understanding
of the molecular mechanisms underlying host-pathogen
interactions.
Table of Contents
Chapter 1.
Background………………………………………………………………1
Background
References………………………………………………28
Background
Figures…………………………………………..............40
Chapter 2. Disabling poxvirus pathogenesis by inhibition of
Abl-family tyrosine
kinases………………………………………………………………….44
Chapter 2
References…………………………………………………71
Chapter 2
Figures……………………………………………………...79
Chapter 3. Variola and monkeypox utilize conserved mechanisms of
virion
motility and release that depend on Abl- and Src-family
tyrosine
kinases………………………………………………………………...106
Chapter 3
References………………………………………………..130
Chapter 3
Tables/Figures……………………………………………133
Chapter 4. Future
Directions…………...………………………………………...146
Chapter 4
References…...………………………………………......152
Chapter 4
figures…...………………………………………………...154
Chapter 5.
Conclusion…………………………………………………………….159
Chapter 5
References………………………..………………………170
About this Dissertation
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