Echovirus 1 replication, not only virus binding to its receptor, VLA-2, is required for the induction of cellular immediate-early genes

Abstract

Induction of immediate-early genes c-jun, junB, and c-fos was demonstrated during echovirus 1 infection in a human osteogenic sarcoma (HOS) cell line. Tenfold induction was seen at 10 h postinfection, corresponding approximately to the end of the first replication cycle of the virus. Echovirus 1 uses VLA-2 integrin as its cellular receptor, and ligand binding by integrin is known to trigger signal transduction pathways ultimately activating immediate-early genes. In the present study, however, VLA-2 binding alone was not sufficient to induce their expression; viral replication was needed. This conclusion was based on the observations that no stimulation of the immediate-early genes occurred in the MG-63 cell line where the virus attached only to VLA-2 but was not able to replicate and that induction of these genes was observed when the HOS cells were infected with echovirus type 7, known to use a different cellular receptor. Induction was not seen in the presence of the antiviral compound WIN 54954, which evidently inhibits the uncoating but not receptor binding of echovirus 1, suggesting that viral replication triggers the activation of the immediate-early genes. The induction of these genes may have a role in viral replication and in the pathogenesis of infection.

Echovirus 1 Infection Induces both Stress- and Growth-Activated Mitogen-Activated Protein Kinase Pathways and Regulates the Transcription of Cellular Immediate-Early Genes

“…Type I collagen and EV1 share the same cellular receptor but induce IE genes by different mechanisms Integrin-matrix interaction is known to mediate integrin clustering and regulate IE genes (Schwartz et al, 1995). EV1 binds to ␣ 2 ␤ 1 integrin, a major collagen receptor in many cells, and we have shown that infection induces mRNA levels of IE genes and that active viral macromolecular synthesis is needed for the induction (Huttunen et al, 1997). To further study this phenomenon, we analyzed junB and c-jun gene activation after adding soluble collagen or EV1 to HOS p␣ 2 AW cells.…”

“…Furthermore, the cells did not spread when plated onto EV1 (not shown), which was in contrast to cells plated onto collagen. Thus, despite the fact that the cells use ␣ 2 ␤ 1 integrin in both collagen and EV1 binding (Huttunen et al, 1997), ligand binding can lead to different cellular consequences. To study whether IE genes are induced when the HOS p␣ 2 AW cells are bound to EV1 without internalization of the virus, we carried out an assay in which cell culture dishes were coated with EV1 or COL I, the cells were allowed to attach for 5 h, and then the levels of c-jun and junB mRNAs were analyzed by Northern blotting.…”

“…Although the infection cycle of some enteroviruses has been studied in detail, cellular consequences of infection are largely unknown. We have recently shown that infections caused by EV1, which uses ␣ 2 ␤ 1 integrin as its cellular receptor (Bergelson et al, 1992), and EV7, which uses decay-accelerating factor (DAF) as its receptor (Bergelson et al, 1994;Ward et al, 1994), are able to induce the cellular immediate-early (IE) genes c-jun, junB, and c-fos in a human osteogenic sarcoma (HOS) cell line (Huttunen et al, 1997).…”

“…We have demonstrated that the mechanism of IE gene induction in EV1 infection differs from that related to type I collagen. The ␣ 2 ␤ 1 integrinmediated cell adhesion to type I collagen is known to increase the expression of IE genes, whereas viral replication, and not integrin±EV1 interaction alone, is required for full-scale induction (Huttunen et al, 1997).…”

Simian varicella virus causes robust transcriptional changes in T cells that support viral replication

“…Moreover, the inhibition of histone demethylase has been shown to block HSV and VZV replication (Liang et al, 2009) and VZV ORF 63 has been shown to regulate histone levels in infected cells (Ambagala et al, 2009). Several of the other upregulated transcription factors that were involved with chromatin assembly such as CFOS, JUNB and JUND were reported to be upregulated with other viral infections such as kaposi's sarcoma-associated herpesvirus (Xie et al, 2008), Epstein-barr virus (Song et al, 2004) measles (Helin et al, 2002), JC virus (Sadowska et al, 2003) and echoviruses (Huttunen et al, 1997).…”