Multiple intracellular pathways triggered by Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infection converge on expression of proinflammatory cytokines and type I Interferon (IFN) response genes. (1) CMV glycoproteins B and H (gB/gH) engage surface TLR-2 and trigger an inflammatory pathway leading to AP-1 activation; (2) cytosolic CMV-DNA interacts with cyclic GMP-AMP synthase (cGAS) and initiates a cascade that targets NFkB and IRF3; (3) CMV nuclear material trafficked to the endosome triggers TLR-7 signaling, leading to IRF-3, -5 and -7 activation; (4) in EBV latency phase, LMP1 induces expression of IR-5, -7 and NFkB; (5) cytosolic EBER-1 is recognised by RIG-1 and MDA-5 and associates with IPS-1 via CARD-like domains, leading to NFkB and IRF3 activation; (6) EBV induces IRF2 and activates ISRE, which codes for EBNA proteins. Legend: MyD88: Myeloid differentiation primary response 88, IKK complex: IkB kinase complex, TRAF: TNF receptor associated factor, AP-1: activator protein-1, EBER-1: EBV-encoded RNA-1; ER: endoplasmic reticulum, cGAS: cyclic GMP-AMP synthase, cGAMP: cyclic guanosine monophosphate-adenosine monophosphate, STING: cyclic GMP-AMP receptor stimulator of interferon genes, TBK: TANK-binding kinase, IRF: interferon regulator factor, LMP1: Epstein–Barr virus latent membrane protein 1, RIG-1: retinoic acid-inducible gene 1, CARD: caspase activation and recruitment domain, MDA5: melanoma differentiation-associated protein-5, IPS-1: interferon-beta promoter stimulator 1, ISRE: IFN-stimulated response element.