Biology Reference
In-Depth Information
Role of Signaling in Pathogenesis
Aberrant signaling and transcription factor regulation is associated with a multitude
of diseases that including birth defects, cancer, and chronic inflammatory diseases
such as cardiovascular disease (Kim et al. 2006). Cell cycle abnormalities are
equally associated with diseases such as cancer and cardiovascular disease (Castillo
and Kowalik 2004; Bentz and Yurochko 2008). Because these same diseases are
associated with or caused by HCMV infection, modulation of multiple signaling
transduction pathways, although beneficial to the virus, may be a molecular mecha-
nism tying HCMV infection to the onset or severity of viral-mediated disease
(reviewed in Evers et al. 2004; DeMeritt and Yurochko 2006; Soderberg-Naucler
2006). Certainly more work is needed to understand the possible direct role that
viral-mediated cellular activation has on the infected host. It is also likely that these
viral-manipulated cellular pathways required for viral pathogenesis may serve as
new therapeutic targets for antiviral agents.
Final Thoughts
Together, it appears that HCMV has evolved a strategy for viral infection, survival,
and persistence within the host that involves a complex biochemical manipulation of
the host. Because of the possibility of severe effects on the host of unchecked signal-
ing, HCMV as an evolutionarily ancient virus may also have evolved a strategy to
mitigate the pathological consequences of this signaling strategy. For example, a
recent report shows that HCMV through the UL83/pp65 tegument protein downreg-
ulates NFκ-B activity (Browne and Shenk 2003). Although this report runs counter
to the data showing that NFκ-B activity is required for viral gene expression
(Caposio et al. 2004, 2007; DeMeritt et al. 2004, 2006; Nogalski et al. 2007), if one
considers that the virus must walk a fine line when activating a cell between those
changes required for viral infection and the activation of cellular antiviral/host
defense pathways and/or pathogenic consequences, these divergent results may rep-
resent two sides of the same coin. Perhaps this is why other reports have shown that
NFκ-B activation negatively regulates or at least does not upregulate MIEP activity
(Benedict et al. 2004; Isomura et al. 2004; Eickhoff and Cotten 2005; Gustems et al.
2006) and that for example the viral gene product, IE2p86, can act as a negative
regulator of some NFκ-B-dependent cellular promoters (Taylor and Bresnahan
2006a, 2006b; Gealy et al. 2007). Using this example as a model, we argue that
Fig. 2
(continued)
productive for viral replication following primary infection, but in response
to the viral-mediated signaling, as represented in the drawing, they differentiate into macrophages
that support viral replication (Smith et al. 2004a), thus both monocytes and their differentiated
counterparts, macrophages, are critical for viral spread and persistence
