Effects of poliovirus infection and picornaviral 3A proteins on the cellular response to viral infection.

摘要

Most pro-inflammatory and antiviral cytokines traffic through the host secretory pathway, and this pathway may be disrupted and/or targeted by viral functions. To investigate potential effects of the known inhibition of cellular protein secretion during poliovirus infection, cytokine secretion from cells infected with wild-type virus and with 3A-2, a virus carrying an insertion mutation in viral protein 3A, which renders the virus defective in the inhibition of protein secretion, was tested. Cells infected with 3A-2 mutant virus secrete greater amounts of cytokines IL-6, IL-8 and interferon-β than cells infected with wild-type poliovirus. Increased cytokine secretion from the mutant-infected cells can be attributed to the reduced inhibition of host protein secretion, because no significant differences between 3A-2 and wild-type infected cells were observed in the inhibition of viral growth, host cell translation, or in the ability of infected cells to support induction of interferon-β mRNA. Therefore, the wild-type function of 3A in inhibiting ER-to-Golgi traffic is not required for viral replication in tissue culture but, by altering the amount of secreted cytokines, could have substantial effects on pathogenesis within an infected host.; Poliovirus is related to a family of viruses that have diverse pathogenic properties. 3A proteins from every genus of picornaviridae were tested for their ability to inhibit secretion. Only the 3A proteins from poliovirus strains 1 and 3 and coxsackievirus B3 significantly inhibited secretion. Since all picornaviruses induce formation of virus-induced vesicles during infection, the lack of secretory inhibition for certain picornaviruses suggests that the inhibition of ER-to-Golgi trafficking by 3A is not obligatorily linked with the formation of vesicles.; Poliovirus infection was also found to inhibit the double-stranded RNA induction of interferon-β mRNA by forty-fold. This inhibition occurs when viral RNA synthesis is inhibited, but not when protein synthesis is inhibited, implying that the inhibition of dsRNA signal transduction is due to the action of a poliovirus protein. cDNA microarrays were used to discover that transcription of almost all genes induced by dsRNA is inhibited during poliovirus infection, providing yet another way by which the virus subverts the host antiviral response.