Cytomegaloviruses (CMV), the prototypical β-herpesviruses, have co-evolved with their
hosts and thus acquired multiple strategies for modulation of the immune response. Viral
engagement of pattern recognition receptors (PRR), such as toll-like receptors (TLRs)
and cytosolic nucleic acids sensors, initiates the host immune response through
activation of elaborate signalling programs. The ensuing inflammatory response is
further sustained and amplified through cytokines, such as IL-1β, activating signalling
pathways greatly overlapping those utilized by TLRs. The central hypothesis of this
thesis is that a viral counter-measure by murine CMV (MCMV) involves specific
targeting of TLR- and IL-1β-induced signalling along the MyD88 to NF-κB pathway.
To test this hypothesis MCMV inhibition of IL-1β signalling was initially investigated in
a fibroblast cell line. It was demonstrated that in MCMV infected cells IL-1β-induced
IκBα degradation is largely inhibited. Comparison of productive and non-productive
infection showed this modulation requires de-novo viral gene expression beyond the
immediate early region. Further investigations utilising a ORF M45 deletion mutant
identified viral gene M45 as necessary for mediating the observed modulation of IL-1β-
induced IκBα degradation. To further test the hypothesis, studies were extended to
include TLR stimulation in the context of bone marrow-derived macrophages (BMDM)
infection. It was found that TLR7/9-induced NF-κB activation is inhibited in MCMV
infected BMDM. Overall, data presented in this study demonstrate a previously
unrecognised MCMV inhibition of IL-1β- and TLR7/9-induced NF-κB activation, and
indicate a role for viral gene M45 in mediating this effect