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The mouse cytomegalovirus G protein-coupled receptor homolog, M33, coordinates key features of ...

The mouse cytomegalovirus G protein-coupled receptor homolog, M33, coordinates key features of in vivo infection via distinct components of its signalling repertoire

Common to all cytomegalovirus (CMV) genomes analysed to date is the presence of G protein-coupled receptors (GPCR). Animal models of CMV provide insights into their role in viral fitness. The mouse cytomegalovirus (MCMV) GPCR, M33, facilitates dendritic cell (DC)-dependent viremia, the extravasation of blood-borne infected DC to the salivary gland and the frequency of reactivation events from latently-infected tissue explants. Constitutive G protein-coupled M33 signalling is required for these phenotypes, although the contribution of distinct biochemical pathways activated by M33 is unknown. M33 engages Gq/11 to constitutively activate phospholipase C β (PLCβ) and downstream cyclic AMP response-element binding protein (CREB) in vitro. Identification of a MCMV M33 mutant (M33ΔC38) for which CREB signalling was disabled, but PLCβ activation was preserved, provided the opportunity to investigate their relevance in vivo. Following intranasal infection with MCMV M33ΔC38, the absence of M33 CREB Gq/11-dependent signalling correlated with reduced mobilisation of lytically-infected DC to draining lymph node high endothelial venules (HEVs) and reduced viremia compared with wild type MCMV. In contrast, M33ΔC38-infected DC within the vascular compartment extravasated to the salivary glands via a pertussis toxin-sensitive, Gi/o-dependent and CREB-independent mechanism. In the context of MCMV latency, spleen explants from M33ΔC38-infected mice were markedly attenuated for reactivation. Taken together, these data demonstrate that key features of the MCMV lifecycle are coordinated in diverse tissues by distinct pathways of the M33 signalling repertoire. IMPORTANCE G protein-coupled receptors (GPCRs) act as cell surface molecular "switches" which regulate the cellular response to environmental stimuli. All cytomegalovirus (CMV) genomes analysed to date possess GPCR homologs with phylogenetic evidence for independent gene capture events, signifying important in vivo roles. The mouse CMV (MCMV) GPCR homolog, designated M33, is important for cell-associated virus spread and for the establishment and/or reactivation of latent MCMV infection. The signalling repertoire of M33 is distinct from cellular GPCRs and little is known of the relevance of component signalling pathways for in vivo M33 function. In this report, we show temporal and tissue-specific M33 signalling is required facilitating in vivo infection. Understanding the relevance of the viral GPCR signalling profiles for in vivo function will provide opportunities for future targeted interventions.

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