The human cytomegalovirus lytic cycle is induced by 1,25-dihydroxyvitamin D3 in peripheral blood monocytes and in the THP-1 monocytic cell line

Abstract

Human cytomegalovirus (HCMV) resides in a latent form in hematopoietic progenitors and undifferentiated cells within the myeloid lineage. Maturation and differentiation along the myeloid lineage triggers lytic replication. Here, we used peripheral blood monocytes and the monocytic cell line THP-1 to investigate the effects of 1,25-dihydroxyvitamin D3 on HCMV replication. Interestingly, 1,25-dihydroxyvitamin D3 induces lytic replication marked by upregulation of HCMV gene expression and production of infectious virus. Moreover, we demonstrate that the effects of 1,25-dihydroxyvitamin D3 correlate with maturation/differentiation of the monocytes and not by directly stimulating the MIEP. These results are somewhat surprising as 1,25-dihydroxyvitamin D3 typically boosts immunity to bacteria and viruses rather than driving the infectious life cycle as it does for HCMV. Defining the signaling pathways kindled by 1,25-dihydroxyvitamin D3 will lead to a better understanding of the underlying molecular mechanisms that determine the fate of HCMV once it infects cells in the myeloid lineage.

The HCMV US28 vGPCR induces potent Gαq/PLC-β signaling in monocytes leading to increased adhesion to endothelial cells

“…Under these infection conditions, we were unable to detect any US28 dependent PLC-β signaling (Figure 2A, left panel). We surmised that the lack of detectable US28 signaling under these conditions might be reflective of the fact that only ~8% of infected THP-1 express viral proteins and the assay is simply not sensitive enough to detect US28-dependent signaling (Wu and Miller, 2015). Treatment with phorbol esters like PMA drives THP-1 cells into more of a macrophage-like phenotype and drives the lytic phase such that ~50% of the infected cells begin to express significant levels of immediate early, early, and late proteins (Wu and Miller, 2015).…”

“…Our studies primarily use inducible US28 expressing THP-1 cells to explore the functional activities and signaling pathways induced by US28 expression because only 5–8% of monocytes or THP-1 cells express HCMV genes after infection (Wu and Miller, 2015) and it is difficult to examine signaling and function when the uninfected cells outnumber the infected cells by such a large margin. In addition, as HCMV encodes over 200 gene products, many of which influence cell signaling and could thereby mask the effects of US28, it is important to first examine US28 function in isolation in specific cell types and then to revisit interesting questions at a later point in the context of infection.…”

The interplay between vitamin D and viral infections

“…In addition to its anti‐inflammatory function, vitamin D could enhance secretion of pro‐inflammatory chemokines (CXCL8 and CXCL10), which may modify the anti‐viral response . Vitamin D treatment of primary monocytes and a monocytic cell line was shown to induce the lytic phase of CMV replication and is thought to be associated with the monocyte maturation/differentiation state …”

Rapid Etiologic Diagnosis of Herpes Virus Infections in Children

“…Serological tests are used in clinics to diagnose EBV, but heterophile antibodies are non-specific and not produced in some patients (17). HCMV is the major cause of congenital infection, affecting 0.3% to 2.3% of newborns, that can lead to severe neurological sequelae such as hearing loss and congenital defects (20,21). It also infects the immunocompromised individuals causing fatal pneumonia and colitis.…”

“…It also infects the immunocompromised individuals causing fatal pneumonia and colitis. What's more, in transplant recipients, HCMV infection not only increases the risk of graft rejection, but also rises the treatment costs (21). Thus, early antiviral interventions can help the body eliminate the pathogens and prevent from establishing latent infections as well as playing an important role in the prevention of CNS infections and pediatric lymphomas.…”