Human Cytomegalovirus Host Interactions: EGFR and Host Cell Signaling Is a Point of Convergence Between Viral Infection and Functional Changes in Infected Cells

Abstract

Viruses have evolved diverse strategies to manipulate cellular signaling pathways in order to promote infection and/or persistence. Human cytomegalovirus (HCMV) possesses a number of unique properties that allow the virus to alter cellular events required for infection of a diverse array of host cell types and long-term persistence. Of specific importance is infection of bone marrow derived and myeloid lineage cells, such as peripheral blood monocytes and CD34+ hematopoietic progenitor cells (HPCs) because of their essential role in dissemination of the virus and for the establishment of latency. Viral induced signaling through the Epidermal Growth Factor Receptor (EGFR) and other receptors such as integrins are key control points for viral-induced cellular changes and productive and latent infection in host organ systems. This review will explore the current understanding of HCMV strategies utilized to hijack cellular signaling pathways, such as EGFR, to promote the wide-spread dissemination and the classic life-long herpesvirus persistence.

Human immunoglobulins are transported to HCMV viral envelope by viral Fc gamma receptors-dependent and independent mechanisms

“…In this scenario, monocytes would be the target population due to their role in dissemination and as reservoir of latent viruses ( Collins-McMillen et al, 2018 ). Upon productive HCMV infection of monocytes, various signaling pathways are induced, among which a key role is played by EGFR-mediated induction of PI(3)K, Akt, N-WASP, NF-κB, and Sp-1, promoting survival and differentiation (reviewed in Lee et al, 2021 ). Monocytes express the activatory receptors, FcγRI, FcγRIIa, and FcγRIIIa, the latter only in 10% of the monocytes, and the inhibitory receptor, FcγRIIb.…”

Cell Fusion and Syncytium Formation in Betaherpesvirus Infection

“…Although subsequent work has indicated that EGFR is more likely to function as a co-receptor [ 148 ], EGFR has initially been proposed as an HCMV entry receptor [ 149 ]. HCMV-induced signaling through the EGFR has been recognized as a key control point for virus–host cell interaction and regulation of both viral and cellular activities [ 150 ]. In addition to EGFR, other receptors such as the platelet-derived growth factor receptor alpha (PDGFRα), Neuropilin-2, olfactory receptor family 14 subfamily I member 1 (OR14I1), and specific integrins and adhesion molecules have been shown to be crucial for HCMV entry [ 151 , 152 , 153 ].…”