295: The differential regulation of the interferon alpha subtypes in response to viral infection

Abstract

The induction of the different interferon alpha (IFNA) subtypes is regulated in a cell type and virus specific manner. Although much work has focused on the transcriptional regulation of the IFNA subtypes, the contribution of the JAK/STAT pathway to the induction and amplification of the different IFNA subtypes remains unknown in humans. To explore this area, we infected 4 different cell lines with VSV, EMCV and SeV and measured the IFNA subtype response as well as the induction of important modulators of the JAK/STAT pathway. Namalwa and U937 cells, which are B and monocytic cell lines, respectively, produced all of the IFNA subtypes in large amounts in response to all 3 viruses. Daudi cells, which are a B cell line, produced between 3 and 6 of the subtypes in moderate amounts depending on the infecting virus. The M059J cells, which are a glioblastoma cell line, produced at most 1 subtype at low levels in response to the viruses. However, despite the vastly different IFNA profiles induced in the different cell types, all of the cells induced comparable amounts of interferon beta (IFNB) and displayed activation of members of the JAK/STAT pathway, including STAT1, IRF3 and IRF7, suggesting that pathways other than the JAK/STAT pathway help regulate the IFNA response. Furthermore, treatment of the cell lines with IFNB to mimic the paracrine amplification loop resulted in vastly different subtype responses. Namalwa and U937 cells, which produced all of the subtypes in large amounts in response to viral infection, only produced 3 and 8 subtypes, respectively, and in very low amounts. Daudi cells only produced very low levels of IFNA21, and the M059J cells did not produce any IFNA. These results suggest that events other than the activation of the JAK/STAT pathway by IFNB may regulate the IFNA subtype response.