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pathways (Smith et al. 2004b; Bentz et al. 2006; Bentz and Yurochko 2008; Chan
et al., unpublished data; Smith et al. 2007). Thus, these signal transduction
pathways do not initially drive viral gene expression in these cell types, but instead
induce cellular changes required for motility and firm adhesion to endothelial cells
and transendothelial migration, suggesting that the biological rationale for the
activation of these pathways is to modulate functional changes in cells of the
vasculature that favor viral spread to and persistence within host organs. The role
EGFR and integrins play in entry and attachment of endothelial cells and mono-
cytes is not clear, although we have data that rapid signaling occurs through these
receptors in both cell types (Bentz and Yurochko 2008; Chan et al., unpublished
data), similar to that seen in fibroblasts (Wang et al. 2003, 2005; Feire et al. 2004),
suggesting that these receptors are globally relevant to infection of multiple cell
types. Overall, we propose that viral-induced signaling creates distinct cell-type-
specific signaling signatures such that viral infection proceeds appropriately in
each cell type (Fig. 2).
Fig. 2
Potential biological outcome of the viral-mediated signaling. Although unresolved, it is
likely that the initially receptor/viral-ligand-mediated signaling promotes viral entry into target
cells, regardless of cell type. This same receptor/ligand-mediated signaling also activates multiple
biochemical pathways in target cells; both common pathways and cell-type-specific pathways are
activated. The other potential mechanisms discussed in this review such as the cellular enzymes
and tegument proteins that come in with the virion, as well as various synthesized viral gene
products, also play a critical role in cellular modification. The net outcome of the viral-mediated
signaling appears to vary depending on the cell type: for example, as represented in this drawing,
productive infection is promoted in fibroblasts, while long-term persistence and survival of the
virus is promoted in endothelial cells and monocytes/macrophages. Note: monocytes are not
