Biology Reference
In-Depth Information
such as cytokines or viruses, activation of the canonical NFκ-B pathway occurs via
signal transduction cascades that promote the phosphorylation and degradation of
inhibitor of NFκ-B proteins (IκBs), thereby releasing the NFκ-B heterodimer. The
activated heterodimer of p50 and p65/Rel A is able to translocate to the nucleus and
drive the expression of target genes (reviewed in Baldwin 1996). Gene inactivation
experiments of individual NFκ-B family members have revealed that Rel A pro-
teins are required for lymphocyte activation by controlling proliferation, immu-
noglobulin isotype switching, and the expression of cytokines and their receptors
(Attar et al. 1997; Gerondakis et al. 1998). Inflammatory cytokines, including
TNF-α, IL-1, IL-6, IL-8, IL-12, and IL-18 have a wide range of biological effects
on tissues and cells and are believed to be critical for the recruitment and activation
of phagocytic leukocytes to the sites of infection (Laroux 2004). Activation of the
IC branch of innate immune signaling is critical for the propagation and elaboration
of cytokine responses.
Fibroblasts and monocytes infected with HCMV exhibit activated NFκ-B, as
evidenced by its nuclear translocation and increased DNA-binding activity
(Yurochko et al. 1995; Yurochko and Huang 1999). HCMV-induced activation
of NFκ-B occurs with rapid kinetics that are suggestive of a receptor-ligand
interaction (Yurochko et al. 1997). Pretreatment of HCMV with neutralizing
antibodies to gB and gH inhibit the induction of the transcription factors NF
κ-B
and Sp1. Moreover, the use of purified gB and an anti-idiotypic antibody to
mimic gH caused the activation of NF
κ-B and Sp1 (Yurochko et al. 1997). These
data coupled with the ability of HCMV to activate innate immune signaling in the
absence of virus replication and cellular protein synthesis led to the hypothesis
that viral glycoproteins are initiating the IC response through receptor-binding
interactions during the entry process.
The activation of NF
κ-B is an immediate host defense mechanism, activated in
response to a myriad of stimuli, including ligand stimulation of the Toll-like recep-
tors (TLRs), a class of key pattern recognition receptors. The primary consequences
of TLR activation are IC secretion, expression of immune co-stimulatory molecules,
dendritic cell maturation, and for a subset of TLRs, interferon α/β activation
(reviewed in Takeda and Akira 2003). Together these factors limit viral replication
to the site of infection, elicit the infiltration of immune cells to the site of infection,
and initiate and modulate adaptive immune responses by T and B cells. To date 12
members of the TLR family have been identified in humans (reviewed in Akira et al.
2006). TLRs are expressed at high levels on phagocytic cells such as dendritic cells
or macrophages; however, all cells express at least a subset of these receptors
(Hornung et al. 2002; Zarember and Godowski 2002). TLRs recognize microbial
pathogens on the basis of structural motifs, termed pathogen-associated molecular
patterns (PAMPs), that differ from those found in the host cell (reviewed in Janeway
and Medzhitov 2002). Examples of PAMPs include lipopolysaccharide (TLR4),
unmethylated CpG DNA (TLR9), and dsRNA (TLR3). Components of a viral enve-
lope can also act as PAMPs to trigger TLR-mediated innate immune signaling. For
example, the fusion protein from respiratory syncytial virus and the envelope protein
of mouse mammary tumor virus are sensed by TLR4 (Kurt-Jones et al. 2000; Burzyn
