Biology Reference
In-Depth Information
FIXBAC (Hahn et al. 2002). On the other hand, involvement on US22 family
members in cell tropism regulation of both HCMV and MCMV indicated a certain
degree of conservation. The contribution of UL24 to endothelial cell tropism of
HCMV strain Towne (Dunn et al. 2003) has already been mentioned. US22-family
members of MCMV, namely m139, m140 and m141 contribute to macrophage
tropism and promote MCMV replication in the spleen of infected mice (Hanson
et al. 2001; Menard et al. 2003). M36, another US22 family gene of MCMV, also
contributes to efficient replication in macrophages again through its anti-apoptotic
function (Menard et al. 2003). Obviously, cell-type-specific inhibition of virus-
induced apoptosis is a more general theme with cytomegaloviruses, suggesting that
similar tropism-relevant anti-apoptotic genes may also exist in the HCMV genome
(see also the chapter by A.L. McCormick, this volume). The HCMV counterpart of
M36, UL36, has a known antiapoptotic function (Skaletskaya et al. 2001), which
has not yet been tested in the context of cell tropism. UL45, the HCMV homolog
of M45, exhibited a weak antiapoptotic activity only upon application of strong
proapoptotic stimuli (Patrone et al. 2003) and was dispensable for viral replication
in endothelial cells (Hahn et al. 2002). However, in vivo the situation may be
different depending on the microenvironment within the infected tissues. In the
presence of strong proapoptotic stimuli, UL36 and UL45 may be essential for
successful completion of viral replication in a cell-type-dependent fashion, as
reported for their murine CMV homologs. Complex cell culture systems reflecting
the situation of an inflamed tissue are required to test this hypothesis.
A specific contribution of rat CMV concerns the role of vascular endothelial cells
and smooth muscle cells in CMV-associated pathogenesis. Under the well-defined
conditions of this animal model, a contribution of vascular CMV infection to the devel-
opment of atherosclerotic lesions is clearly shown and the molecular mechanisms are
partially deciphered, including oxLDL uptake, altering monocyte adhesion or increas-
ing the production of pro-inflammatory cytokines (Stassen et al. 2006). In the human
system, it may be impossible to prove the contribution of HCMV to a multifactorial
disease such as atherosclerosis under natural clinical conditions. However, similarities
between RCMV and HCMV regarding cytopathic effects in vascular cell types never-
theless suggest CMV as a proatherosclerotic agent also in humans.
Impact of Cell Tropism Analyses
The ability of CMV species to infect a variety of different cell types in their respec-
tive host appears to be central for successful entry, dissemination, persistence,
reactivation and excretion. Analyzing CMV replication in various cell culture
systems is therefore an absolute requirement for a comprehensive understanding of
their biology and will in itself create additional value. Particularly, many of the
genes still classified nonessential with regard to replication in the standard cell
culture system will turn out to be essential if tested in other cell types or in
complex tissues composed of several interacting cell types.
