Disabling Poxvirus Pathogenesis Pubblico
Reeves, Patrick (2009)
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
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