Cytomegalovirus Enhances Macrophage TLR Expression and MyD88-Mediated Signal Transduction To Potentiate Inducible Inflammatory Responses

Abstract

Circulating monocytes carrying human cytomegalovirus (HCMV) migrate into tissues, where they differentiate into HCMV-infected resident macrophages that upon interaction with bacterial products may potentiate tissue inflammation. Here we investigated the mechanism by which HCMV promotes macrophage-orchestrated inflammation using a clinical isolate of HCMV (TR) and macrophages derived from primary human monocytes. HCMV infection of the macrophages, which was associated with viral DNA replication, significantly enhanced TNF-α, IL-6 and IL-8 gene expression and protein production in response to TLR4 ligand (lipopolysaccharide, LPS) stimulation compared with mock-infected LPS-stimulated macrophages during a 6-day in vitro infection. HCMV infection also potentiated TLR5 ligand-stimulated cytokine production. To elucidate the mechanism by which HCMV infection potentiated inducible macrophage responses, we show that infection by HCMV promoted the maintenance of surface CD14 and TLR4 and 5, which declined over time in mock-infected macrophages, and enhanced both the intracellular expression of adaptor protein MyD88 and the inducible phosphorylation of IκBα and NF-κB. These findings provide additional information toward elucidating the mechanism by which HCMV potentiates bacteria-induced NF-κB-mediated macrophage inflammatory responses, thereby enhancing organ inflammation in HCMV-infected tissues.

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

“…In the absence of HIV-1, induction of replicating CMV has been shown to occur with the terminal differentiation of monocytes to myeloid dendritic cells, 49 and in vitro studies have demonstrated that monocyte to macrophage differentiation leads to production of infectious virus. [50][51][52] If HIV-1 infection activates monocytes and macrophages, 53 it is likely that CMV could be reactivated and replicate leading to an inflammatory response. In our study the association of CMV IgG with sCD14 within the HIV-1 viremic group, which was not present in the HIV-uninfected group, suggests that coinfection and long-term interaction of HIV-1 and CMV may lead to the development of serious non-AIDS events.…”

“…50 Reactivation of CMV may result in production of biomarkers of inflammation and immune activation such as sCD14, IL-6, sCD163, and IP10. 22,47,51,57 An increase in CMV IgG and CMV-specific T cells may result in temporary control of infection, but the potential for additional cycles of reactivation and inflammation would be predicted to result in cellular and tissue damage. The extent of the damage would depend on the body compartment(s) involved and the magnitude and frequency of the immunological response to the infections.…”

Cell-type specific activities of cytomegalovirus GPCR homologues

“…When expression of chemokines is compared between infected and transfected HUVEC, quite a few more chemokines could be detected in infected cells, supporting previous studies of upregulation of growth factors/chemokine/cytokines following HCMV infection (Frascaroli et al, 2006;Hamilton et al, 2012;Li et al, 2014;Murayama et al, 1997;Scott et al, 2012;Smith et al, 2014;Weseslindtner et al, 2014). Indeed, we found 18 chemokines elevated in HCMV-infected HUVEC.…”

Mucosal Macrophages in Defense and Regulation

“…Infection with CMV enhances monocyte transendothelial migration and motility (Smith et al, 2004a(Smith et al, , 2007, as well as monocyte differentiation into macrophages (Smith et al, 2004a,b;Chan et al, 2012), thereby promoting the dissemination of CMV-infected mononuclear phagocytes to the tissues. In addition, CMV infection upregulates macrophage expression of surface CD14 and TLRs 2, 4, and 5 and enhances the capacity of monocyte-derived macrophages to produce inflammatory cytokines in response to the cognate TLR ligands L. monocytogenes, Escherichia coli lipopolysaccharide, and Salmonella typhimurium flagellin ( Smith et al, 2014). Infection of macrophages with CMV induces adaptor protein MyD88 expression and enhances inducible phosphorylation of IκBα and NF-κB, promoting the translocation of NF-κB p65 into the nucleus for activation of inflammatory cytokine genes and the production of proinflammatory cytokines (Smith et al, 2014).…”

“…In addition, CMV infection upregulates macrophage expression of surface CD14 and TLRs 2, 4, and 5 and enhances the capacity of monocyte-derived macrophages to produce inflammatory cytokines in response to the cognate TLR ligands L. monocytogenes, Escherichia coli lipopolysaccharide, and Salmonella typhimurium flagellin ( Smith et al, 2014). Infection of macrophages with CMV induces adaptor protein MyD88 expression and enhances inducible phosphorylation of IκBα and NF-κB, promoting the translocation of NF-κB p65 into the nucleus for activation of inflammatory cytokine genes and the production of proinflammatory cytokines (Smith et al, 2014). These findings indicate a mechanism by which CMV potentiates bacteriainduced proinflammatory cytokines and chemokines by monocyte-derived macrophages (Smith et al, 1992;Peterson et al, 1992;Yurochko and Huang, 1999;Redman et al, 2002;Kossmann et al, 2003;Maheshwari et al, 2006).…”