Human cytomegalovirus induction of a unique signalsome during viral entry into monocytes mediates distinct functional changes: a strategy for viral dissemination

Abstract

Review on the viral entry process of HCMV and the potential role of receptor-ligand interactions in modulating monocyte biology. HCMV pathogenesis is a direct consequence of the hematogenous dissemination of the virus to multiple host organ sites. The presence of infected monocytes in the peripheral blood and organs of individuals exhibiting primary HCMV infection have long suggested that these blood sentinels are responsible for mediating viral spread. Despite monocytes being “at the right place at the right time”, their short lifespan and the lack of productive viral infection in these cells complicate this scenario of a monocyte-driven approach to viral dissemination by HCMV. However, our laboratory has provided evidence that HCMV infection is able to induce a highly controlled polarization of monocytes toward a unique and long-lived proinflammatory macrophage, which we have demonstrated to be permissive for viral replication. These observations suggest that HCMV has evolved as a distinct mechanism to induce select proinflammatory characteristics that provide infected monocytes with the necessary tools to mediate viral spread following a primary infection. In the absence of viral gene products during the early stages of infection, the process by which HCMV “tunes” the inflammatory response in infected monocytes to promote viral spread and subsequently, viral persistence remains unclear. In this current review, we focus on the viral entry process of HCMV and the potential role of receptor-ligand interactions in modulating monocyte biology. Specifically, we examine the signaling pathways initiated by the distinct combination of cellular receptors simultaneously engaged and activated by HCMV during viral entry and how the acquisition of this distinct signalsome results in a nontraditional activation of monocytes leading to the induction of the unique, functional attributes observed in monocytes following HCMV infection.

Human Cytomegalovirus Stimulates the Synthesis of Select Akt-Dependent Antiapoptotic Proteins during Viral Entry To Promote Survival of Infected Monocytes

“…4F), indicating that increased transcription is not the only mechanism regulating protein expression. Nonetheless, since we have previously shown gH-initiated signaling to cross talk with EGFR (19), these data suggest that EGFR activation through both direct gB binding and indirect gH cross talk, as well as integrin activation through gH, is required for the increase in Mcl-1 and HSP27 mRNA levels.…”

“…Myeloid differentiation factors granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) block the activation of caspase 3 prior to the 48-h viability checkpoint (14,17). Similarly, we found that HCMV infection inhibited the activation of caspase 3 for the first 48 h postinfection (hpi), facilitating an antiapoptotic state and promoting monocyte-to-macrophage differentiation (14,18,19). The survival of infected short-lived monocytes is crucial for viral spread since, unlike monocytes, macrophages are permissive to viral replication (20)(21)(22)(23).…”

“…2A and B). HCMV gB and gH bind to EGFR and ␣v␤3, respectively, to initiate PI3K/Akt signaling (19,(34)(35)(36)40), suggesting that gBand gH-initiated signaling may cooperatively regulate Mcl-1 and HSP27 expression following HCMV infection of monocytes. Indeed, HCMV particles coated with neutralizing gB or gH antibodies was unable to induce Mcl-1 and HSP27 (Fig.…”

“…Akt (the downstream target of PI3K) substrate specificity is regulated by the phosphorylation ratio of two phosphorylation sites, indicating that upstream signaling events are key determinants to the functional outcome of PI3K signaling (32,33). HCMV directly stimulates monocyte PI3K/Akt signaling as a result of HCMV glycoprotein gB binding to the cellular epidermal growth factor receptor (EGFR) (19,34,35). We have also shown that unidirectional cross talk to EGFR from gH engagement of ␣v␤3 integrin also contributes to PI3K/ Akt signal strength, which is in contrast to bidirectional cross talk that occurs between EGFR and ␣v␤3 during viral entry into fibroblasts (19,36).…”

“…HCMV directly stimulates monocyte PI3K/Akt signaling as a result of HCMV glycoprotein gB binding to the cellular epidermal growth factor receptor (EGFR) (19,34,35). We have also shown that unidirectional cross talk to EGFR from gH engagement of ␣v␤3 integrin also contributes to PI3K/ Akt signal strength, which is in contrast to bidirectional cross talk that occurs between EGFR and ␣v␤3 during viral entry into fibroblasts (19,36). However, the mechanism by which this virus-specific signalsome generated during viral entry into monocytes induces Mcl-1 and HSP27 expression in order to stimulate the survival of infected cells is unclear.…”