|dc.description.abstract||The murine cytomegalovirus (MCMV) immediate early 1 (IE1) protein has been
described as a trans-activator of viral and host gene expression. However, the
precise role that IE1 plays in the viral life cycle, and in particular its effect on
the host immune response is not known. This thesis investigates the functional
relationship of the IE1 protein and the immune response induced after infection.
By using an ie1-deletion mutant MCMV (MCMVdie1) it was demonstrated
that, early after infection, tumor necrosis factor (tnf ) gene activation and protein
production was significantly induced in infected-primary macrophages (M ) to
a much greater extent than its wild type counterpart. In addition, preliminary
studies on the signalling pathways activated upon infection were carried out in
order to gain information about the pathways that might be involved in MCMVinduced
modulation of tnf activation. Initial observations on the MAPK family
members Erk1/2, p38 and JNK did not revealed any differential activation in the
absence of IE1. However, due to a number of limitations, it was not possible to
draw any firm conclusions from this study.
Investigation of the role of IE1 in the in vivo production of TNF were also
performed in both susceptible (BALB/c) and resistant (C57Bl/6) mice. These experiments
confirmed the attenuated phenotype of MCMVdie1 in vivo, whereby
the mutant strain grew to much lower titers than wild type. When cytokine production
was assessed in relation to PFU levels a significant production of TNF
after infection is observed in different organs of both mice strains. This raises
the question whether IE1 contributes to MCMV modulation of TNF production
in the natural host. Although, because it is still unclear whether the phenotype
of MCMVdie1 in vivo is due to a defect in the virus or the result of a immune response, it was not possible to conclude unequivocally that IE1 is responsible
for dampening this cytokine response.
This thesis also tested whether the attenuated replication of MCMVdie1 in
vivo was due to the increased TNF production induced after infection. An initial
investigation in tnf depleted mice revealed that the MCMVdie1 growth phenotype
is not due to TNF response.
Overall, this study has provided insight into a potential immune modulatory
function by MCMV associated with IE1 protein and the regulation of TNF in vivo
and in vitro.||en