Abstract
The wide range of disease pathologies seen in multiple organ sites associated with human cytomegalovirus (HCMV) infection results from the systemic hematogenous dissemination of the virus, which is mediated predominately by infected monocytes. In addition to their role in viral spread, infected monocytes are also known to play a key role in viral latency and life-long persistence. However, in order to utilize infected monocytes for viral spread and persistence, HCMV must overcome a number of monocyte biological hurdles, including their naturally short lifespan and their inability to support viral gene expression and replication. Our laboratory has shown that HCMV is able to manipulate the biology of infected monocytes in order to overcome these biological hurdles by inducing the survival and differentiation of infected monocytes into long-lived macrophages capable of supporting viral gene expression and replication. In this current review, we describe the unique aspects of how HCMV promotes monocyte survival and differentiation by inducing a “finely-tuned” macrophage cell type following infection. Specifically, we describe the induction of a uniquely polarized macrophage subset from infected monocytes, which we argue is the ideal cellular environment for the initiation of viral gene expression and replication and, ultimately, viral spread and persistence within the infected host.
Highlights
Human cytomegalovirus (HCMV), a ubiquitous betaherpesvirus that infects 60%–90% of the population worldwide, establishes a lifelong infection of the host [1]
The precise mechanisms for how human cytomegalovirus (HCMV) directs the polarization of infected monocytes/macrophages remain undetermined, our data clearly indicate that HCMV serves as a unique ligand that induces the differentiation and polarization of infected monocytes/macrophages towards a distinct phenotype that shares common characteristics with both M1 and M2 polarized macrophages [78,79] (Figures 2 and 3)
HCMV appears to regulate the polarization of infected monocytes/macrophages in order to achieve an effective balance between pro-inflammatory and anti-inflammatory signals, which may establish the cellular environment that is conducive for dissemination and persistence of HCMV (Figure 5)
Summary
Human cytomegalovirus (HCMV), a ubiquitous betaherpesvirus that infects 60%–90% of the population worldwide, establishes a lifelong infection of the host [1]. We propose that HCMV modulates the polarization of infected monocytes/macrophages to induce an activated, mostly M1-like phenotype in order to promote the pro-inflammatory changes (such as adhesion, motility, and survival) that are required for effective viral dissemination while dampening a potential anti-viral immune response by promoting the upregulation of key M2-associated genes (such as IL-10 and CCL18). We predict that the early pro-inflammatory phenotype of HCMV-infected monocytes/macrophages regulates the motility and migration of the infected cells in order to promote their exit out of the bloodstream, and it helps to trigger the pro-survival signals necessary to overcome the cell’s intrinsic apoptotic program (inflammatory activation is known to induce prolonged monocyte survival [90]). We predict that the expression of M1-associated cytokines likely promotes the required biological changes for enhanced motility, transendothelial migration, and survival to promote viral spread and replication and to help provide resistance to any later production of these pro-inflammatory cytokines, while the expression of M2-associated cytokines promotes an environment that is better-suited for viral replication and that helps to dampen immune detection of the virus
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