HCMV activates PI(3)K in monocytes and promotes monocyte motility and transendothelial migration in a PI(3)K-dependent manner

Abstract

Human cytomegalovirus (HCMV) is a leading cause of morbidity and mortality in immunocompromised hosts. In immunocompetent hosts, HCMV is associated with chronic inflammatory diseases including atherosclerosis. Monocytes and macrophages are proposed to play key roles in HCMV dissemination to host tissue, and their infection provides a biological link between the lifecycle of HCMV and disease pathology. We hypothesize that viral spread occurs via a mechanism in which infected peripheral blood monocytes, which are nonpermissive for viral replication, extravasate into host tissue and subsequently differentiate into permissive macrophages. Supporting this hypothesis, we recently showed that HCMV specifically induced the differentiation of monocytes into macrophages that become permissive for viral replication. To expand our understanding of HCMV pathogenesis, we next examined monocyte activation and migration, the first events in viral pathogenesis. We show here that HCMV up-regulates phosphatidylinositol 3,4,5 triphosphate kinase [PI(3)K] activity and that this increased PI(3)K activity is essential for infected monocyte-transendothelial migration. This increase in migration occurs through the up-regulation of cell motility in a PI(3)K-dependent process. Last, we show that these activated monocytes express a number of inflammatory mediators via PI(3)K signaling. We propose that the up-regulation of monocyte migration and immune mediators by HCMV infection is required for the hematogenous dissemination of the virus and as a consequence, could promote chronic inflammatory diseases associated with HCMV infection.

Human cytomegalovirus activation of ERK and myeloid cell leukemia-1 protein correlates with survival of latently infected cells

“…Our data suggest that MCL-1 is an attractive target for the establishment of latency. Interestingly, HCMV has also been shown to activate the PI3K pathway in both permissive (10) and nonpermissive infection (40), which suggested that the protective effects of HCMV we observed could be mediated via this pathway also. Although we cannot preclude a role for the activation of these pathways in aspects of cell survival, in our hands, it was the ERK pathway that appeared important for initial survival of latently infected CD34 + cells in response to infection or the further stress of cisplatin A. Interestingly, the pathogenesis of chronic myeloid leukemia has also been associated with the activation of MCL-1 expression in an ERK-, but not PI3K-, dependent manner consistent with ERK-induced activation of MCL-1 being important for early myeloid cell survival (41).…”

Activation of EGFR on monocytes is required for human cytomegalovirus entry and mediates cellular motility

“…3B). Pretreatment with the DMSO solvent control (3,5) or the IgG isotype-matched control did not affect HCMV-induced motility. Similar results were observed when EGF was used as the activating ligand, further supporting the role that EGFR plays in directly modulating monocyte motility (Fig.…”

“…The 2.5-fold induction in transendothelial migration by HCMV or EGF was abrogated by inhibition of EGFR signaling. Pretreatment with the DMSO solvent control (3,5) or the IgG isotype-matched control antibody did not affect HCMV-induced monocyte transendothelial migration. Together, these data show that EGFR possesses biological functions in human peripheral blood monocytes and are consistent with our hypothesis that EGFR engagement by the virus triggers changes in monocytes to promote hematogenous dissemination.…”

“…Monocytes are primary in vivo targets for HCMV and are believed to be responsible for hematogenous dissemination of HCMV to multiple organ systems (2). We previously showed that HCMV infection of monocytes polarized the infected cell toward a distinct proinflammatory phenotype that possessed the distinct biological changes necessary to promote viral spread (3)(4)(5). Specifically, HCMV infection induced polarization of infected monocytes toward an M1 proinflammatory cell type that simultaneously exhibited characteristics associated with an M2 antiinflammatory macrophage (6).…”

HCMV-Encoded UL128 Enhances TNF-α and IL-6 Expression and Promotes PBMC Proliferation Through the MAPK/ERK PathwayIn Vitro

“…The precise function of UL128 on host immune cells remains unknown. Recent evidence shows that HCMV may upregulate cellular gene products associated with monocyte extravasation and inflammation, such as adhesion molecules, inflammatory cytokines, chemokines, and chemokine receptors in a PI(3)K-dependent manner (13,14). Our objective was to determine if HCMV-encoded UL128 interferes with the initiating steps in the host immune response, or if it modulates the function of host inflammatory cells.…”