Biological Rationale for Modulation of Host Cell Signaling

There is little doubt that HCMV binding and/or infection of multiple cell types induces a sequence of signaling events (more detail provided in DeMeritt and Yurochko 2006), of which key points have been discussed briefly above. The question that remains is why the virus has evolved an elaborate strategy involving a multitiered approach to activate host target cells? The available evidence suggests the viral-induced signaling serves to promote multiple steps required for an efficient infection cycle. In human diploid fibroblasts, gB and gH stimulate signal transduction pathways required for viral entry (Wang et al. 2003, 2005; Feire et al. 2004), demonstrating that rapid signaling serves initially to stimulate entry. The same pathways required for this essential first step in the infection process (the activation of the EGFR kinase and Src via binding to EGFR and the integrins, respectively) also rapidly induce transcription factors such as NFk-B. In our model, this induction is required for efficient transactivation of the MIEP and the production of viral IE gene products (DeMeritt et al. 2004), as well as the later viral gene classes (DeMeritt et al. 2006). It is likely that this facet of the viral biology, the activation of required host cell factors (transcription factors, cell cycle regulators, etc.) through the targeted specific activation of signal transduction pathways, is repeated for other specific pathways documented to be activated during infection of target cells. For example, additional transcription factors such as Sp1 are also induced following viral binding to promote the transactivation of the MIEP (Isomura et al. 2005; Yurochko et al. 1997a, 1997b). Because other signaling players such as the virion-associated CKII (Nogalski et al. 2007) and various tegument proteins (Romanowski et al. 1997; Stamminger et al. 2002; Schierling et al. 2004; Cantrell and Bresnahan 2006a; Feng et al. 2006; Munger et al. 2006; Saffert and Kalejta 2006) also promote the efficient expression of the IE gene products, it appears that multiple signaling pathways, although biochemically distinct, coordinate their efforts to focus on a single goal for the virus such as the upregulation of the MIEP and the initiation of the viral gene cascade. Other steps in the viral infection cycle are also essential to the infection process; thus it is likely that additional viral-mediated signaling pathways converge on a common molecular outcome to benefit the virus. An example is the role various tegument proteins and IE gene products play in ensuring that the required cellular replicative enzymes are available for viral replication (Castillo and Kowalik 2004).

Different cell types have distinct signaling capabilities, and even the same signal transduction pathway can have divergent downstream consequences in different cell types. Thus, we hypothesize that the viral regulation of signaling pathways will have different outcomes in cells such as endothelial cells and monocytes, which are critical cells for in vivo infection. We recently provided evidence for a unique two-pronged strategy for hematogenous dissemination involving endothelial cells and monocytes: (1) HCMV directly infects vascular endothelial cells (see references within Bentz et al. 2006; Mocarski et al. 2007; C. Sinzger et al., this volume), which in turn promotes naive monocyte transendothelial migration and viral transfer to these migrating monocytes (Bentz et al. 2006), and (2) HCMV directly infects peripheral blood monocytes in order to promote their transendothelial migration (Smith et al. 2004a). Following transendothelial migration, both pools of infected monocytes differentiate into pro-inflammatory macrophages permissive for the replication of the original input virus, even though the original undifferentiated monocyte was not permissive for viral replication at the time of infection. The virus initiates these functional changes in endothelial cells and monocytes through the binding of viral glycoproteins to EGFR and cellular integrins and the resulting modulation of downstream signaling cascades such as the PI(3)K and NFk-B

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

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

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