The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-triggered Secretion of IL-6

Abstract

The successful establishment and maintenance of human cytomegalovirus (HCMV) latency is dependent on the expression of a subset of viral genes. Whilst the exact spectrum and functions of these genes are far from clear, inroads have been made for protein-coding genes. In contrast, little is known about the expression of non-coding RNAs. Here we show that HCMV encoded miRNAs are expressed de novo during latent infection of primary myeloid cells. Furthermore, we demonstrate that miR-UL148D, one of the most highly expressed viral miRNAs during latent infection, directly targets the cellular receptor ACVR1B of the activin signalling axis. Consistent with this, we observed upregulation of ACVR1B expression during latent infection with a miR-UL148D deletion virus (ΔmiR-UL148D). Importantly, we observed that monocytes latently infected with ΔmiR-UL148D are more responsive to activin A stimulation, as demonstrated by their increased secretion of IL-6. Collectively, our data indicates miR-UL148D inhibits ACVR1B expression in latently infected cells to limit proinflammatory cytokine secretion, perhaps as an immune evasion strategy or to postpone cytokine-induced reactivation until conditions are more favourable. This is the first demonstration of an HCMV miRNA function during latency in primary myeloid cells, implicating that small RNA species may contribute significantly to latent infection.

Defining the Transcriptional Landscape during Cytomegalovirus Latency with Single-Cell RNA Sequencing

“…Infected monocytes expressed relatively high level of UL138 while showing only trace level of IE1 transcript ( Fig. 2A), thus manifesting the hallmark of latent infection (25,27,28,33,43,44). Our latently infected monocytes release only trace amount of infectious virus, while differentiation of these infected monocytes into dendritic cells resulted in detectable IE expression as well as production of infectious virions ( Fig.…”

Human Cytomegalovirus miR-UL148D Facilitates Latent Viral Infection by Targeting Host Cell Immediate Early Response Gene 5

“…Therefore, the expression level and potential function of miR-UL148D during HCMV latency could be further studied using in vivo system in the future. Moreover, while this manuscript was under review, Lau et al also reported that miR-UL148D is expressed during latency and demonstrated that miR-UL148D could limit proinflammatory cytokine secretion of latently infected cells by inhibiting ACVR1B expression[73], which suggests that miR-UL148D may exert multiple function to facilitate viral latent infection. The future study could further explore the multiple role of miR-UL148D in the viral latency.…”

MicroRNA Involvement in Signaling Pathways During Viral Infection

“…Furthermore, two fairly newly discovered HCMV miRNAs, miR-US5-1 and miR-UL112-3p, have recently been shown to target members of the IκB kinase (IKK) complex, IKKα and IKKβ, therefore reducing NF-κB signaling during late infection (Hancock et al, 2017) and, consequently, the expression of proinflammatory genes encoding cytokines and chemokines (Liu et al, 2017). The secretion of cytokines and chemokines including IL-6 is further inhibited by miR-UL148D, viral miRNA that has been shown to be predominantly expressed during latency (Lau et al, 2016;Goodwin et al, 2018).…”