Poliovirus 3A protein limits interleukin-6 (IL-6), IL-8, and beta interferon secretion during viral infection

During viral infections, the host secretory pathway is crucial for both inn ate and acquired immune responses. For example, the export of most proinfla mmatory and antiviral cytokines, which recruit lymphocytes and initiate ant iviral defenses, requires traffic through the host secretory pathway. To in vestigate potential effects of the known inhibition of cellular protein sec retion during poliovirus infection on pathogenesis, cytokine secretion from cells infected with wild-type virus and with 3A-2, a mutant virus carrying an insertion in viral protein 3A which renders the virus defective in the inhibition of protein secretion, was tested. We show here that cells infect ed with 3A-2 mutant virus secrete greater amounts of cytokines interleukin- 6 (IL-6), IL-8, and beta interferon than cells infected with wild-type poli ovirus. 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 obs erved in the inhibition of viral growth, host cell translation, or the abil ity of wild-type- or 3A-2-infected cells to support the transcriptional ind uction of beta interferon mRNA. We surmise that the wild-type function of 3 A in inhibiting ER-to-Golgi traffic is not required for viral replication i n tissue culture but, by altering the amount of secreted cytokines, could h ave substantial effects on pathogenesis within an infected host. The global inhibition of protein secretion by poliovirus may reflect a general mechan ism by which pathogens that do not require a functional protein secretory a pparatus can reduce the native immune response and inflammation associated with infection.