Transforming growth factor-beta-mediated regulation of BK virus gene expression

Abstract

The increasing prevalence of BK virus (BKV)-associated diseases in immunosuppressed patients has prompted an investigation of the immune response to BKV, especially the role of cytokines in regulating viral replication. We examined the effect of TGF-beta, a cytokine that is stimulated by certain immunosuppressive therapies, on BKV gene expression during lytic infection of renal proximal tubule epithelial cells. Viral gene expression, and specifically the activity of the BKV early promoter, is regulated by TGF-beta in a strain-dependent manner. Promoter activity is upregulated in the presence of TGF-beta for the TU strain of BKV, and not for the Dik, Dunlop, or Proto-2 strains. Using site-directed mutagenesis, we have identified a small segment of the TU promoter that is required for stimulation in response to TGF-beta. These results demonstrate that BKV strains can respond differently to cytokine treatment and suggest that TGF-beta may play a role in the reactivation of BKV.

Transforming Growth Factor β-Induced Reactivation of Epstein-Barr Virus Involves Multiple Smad-Binding Elements Cooperatively Activating Expression of the Latent-Lytic SwitchBZLF1Gene

“…Elevated levels of TGF-␤ are observed after treatment with immunosuppressive drugs such as cyclosporine. TGF-␤ induces the expression of the virus-encoded large tumor antigen in renal cells infected with the TU strain of BK virus, doing so via adjacent putative ZEB-and Smad-binding elements present in the promoter region of this gene (1). These findings suggest that many DNA viruses utilize a similar mechanism to regulate reactivation into lytic replication by TGF-␤.…”

Polyomavirus Reactivation in Pediatric Patients with Systemic Lupus Erythematosus

“…As in vitro studies have shown that TGF-β1 stimulates JC and BK reactivation in many cell cultures (Ravichandran et al 2007;Abend and Imperiale 2008;Stettner et al 2009), TGF-β1 could be an important cytokine that regulates JC and BK reactivation in SLE. TGF-β is an anti-inflammatory cytokine with three isoforms sharing similar functions namely TGF-β1 which is most abundant, TGF-β2 and TGF-β3 (Tyagi et al 2009).…”

“…At the molecular level, administration of cyclosporine A and tacrolimus has been shown to increase transforming growth factor (TGF)-β1 expression (Shihab et al 1996;Khanna et al 1999). TGF-β1, an isoform of TGF-β, is involved in the regulation of cell proliferation, differentiation and immune suppression (Abend and Imperiale 2008). In cell cultures, TGF-β1 can enhance JC and BK reactivation in human glial cells and renal tubular cells (Ravichandran et al 2007;Abend and Imperiale 2008).…”

“…TGF-β1, an isoform of TGF-β, is involved in the regulation of cell proliferation, differentiation and immune suppression (Abend and Imperiale 2008). In cell cultures, TGF-β1 can enhance JC and BK reactivation in human glial cells and renal tubular cells (Ravichandran et al 2007;Abend and Imperiale 2008). However, the role of TGF-β1 in PyV reactivation in SLE requires further investigation.…”

Reovirus Activates Transforming Growth Factor β and Bone Morphogenetic Protein Signaling Pathways in the Central Nervous System That Contribute to Neuronal Survival following Infection

“…In addition, TGF-␤ signaling controls apoptosis and viral replication in several viral systems including polyomaviruses such as BK virus (1) and JC virus (16,30), human immunodeficiency virus (16), EpsteinBarr virus reactivation (17), and hepatitis C virus (26). In the case of hepatitis C virus, the synergistic activation of BMP signaling and alpha interferon suppresses viral replication (35).…”