Biology Reference
In-Depth Information
(Boyle and Compton 1998). This secondary binding interaction could be through a
gB-EGFR, gB-β1 integrin interaction, or both. However, the role of EGFR in HCMV
entry remains uncertain and integrins may act at a post-binding/fusion step; therefore,
there is most likely an additional cellular receptor(s) yet to be discovered. It is believed
that receptor clustering and signaling may occur following the engagement of cellular
integrins by gB and gH, leading to many downstream signaling events necessary for
virus entry and/or gene expression (Feire et al. 2004; Wang et al. 2005). Last, gH/gL/
gO along with gB mediate the fusion of the viral and cellular membranes, most likely
through gB and gH interactions with cellular integrins (Keay and Baldwin 1991;
Navarro et al. 1993; Bold et al. 1996; Feire et al. 2004; Wang et al. 2005).
Introduction to Activation of Innate Immunity
Early events in HCMV infection cause a global reprogramming of cellular transcrip-
tion (Zhu et al. 1997, 1998; Browne et al. 2001; Simmen et al. 2001). Binding and
entry of HCMV are known to cause physiological changes such as transient influx
of Ca 2+ , activation of phospholipases C and A2, and the stimulation of arachidonic
A metabolism (reviewed in Fortunato et al. 2000). Binding of HCMV envelope
glycoproteins to cellular receptors can initiate signal transduction pathways leading
to the activation of cellular transcription factors such as NFκ-B, Sp1, and interferon
regulatory factor 3 (IRF3) (Yurochko et al. 1997; Navarro et al. 1998; Boehme et al.
2004, 2006). Large-scale studies have revealed that hundreds of cellular genes are
affected by early events in HCMV entry and the most strongly induced are antiviral
genes belonging to the inflammatory cytokine (IC) family and the interferon-
stimulated gene (ISG) family, such as those for RANTES, interleukin-6 (IL-6), IL-8,
ISG-54-kDa protein, and IRF-7 (Zhu et al. 1997, 1998; Browne et al. 2001; Simmen
et al. 2001). Both of these classes of molecules are hallmarks of innate immunity and
contribute significantly to control infection (Stark et al. 1998; Sen 2001). The robust
induction of innate immune responses by HCMV does not require virus replication
or cellular protein synthesis, suggesting that structural components of the virus are
responsible for the changes in gene expression during virus-cell contact and/or entry
(Zhu et al. 1997; Browne et al. 2001). Treatment of fibroblasts with glycoprotein B
results in a strikingly similar gene expression profile as cells treated with recom-
binant interferons (Simmen et al. 2001). Together these innate immune responses
serve to limit viral replication early during infection as well as activate and promote
adaptive immune responses that will ultimately contain or clear the infection.
Activation of Inflammatory Cytokines
The IC branch of the innate immune response is defined by the activation of NFκ-B,
which is responsible for the transcription of genes encoding many pro-inflammatory
cytokines and chemokines (reviewed in Hayden et al. 2006). In response to stimuli
Search WWH ::




Custom Search