Autocrine Interferon Priming in Macrophages but Not Dendritic Cells Results in Enhanced Cytokine and Chemokine Production after Coronavirus Infection

Zhou, Haixia; Zhao, Jincun; Perlman, Stanley

associated proteins, and one to eight accessory proteins (proteins interspersed between or within structural proteins encoded at the 3= end of the genome). SARS-CoV (severe acute respiratory syndrome coronavirus) accessory proteins ORF3b and ORF6, mouse hepatitis virus (MHV) accessory protein ORF5a, MHV and SARS-CoV nucleocapsid (N) proteins and replicase-associated nonstructural protein 1 (nsp1) and nsp3 are all able to inhibit IFN induction and/or signaling (9-15) (reviewed in reference 16) . In addition, MHV delays IFN-stimulated gene (ISG) induction by IFN or Sendai virus (SenV) (17) . Further, in some cell types, including fibroblasts and cDC, neither SARS-CoV nor MHV induces IFN expression. However, neither virus is able to prevent IFN induction by other viruses or by poly(I · C), which suggests that these viruses are "invisible" to intracellular IFN sensors (18, 19) . This "passive" method of immune evasion may occur because coronaviruses replicate on membranous structures, including double-membrane vesicles, thereby limiting exposure of sequestered RNA to innate immune sensors (18) (19) (20) . On first glance, these results appeared to contradict the observation that type I IFNs are detected in MHV-infected mice and in patients with SARS (21, 22) . However, IFN is induced in pDC by a TLR7-and interferon regulatory factor 7 (IRF7)-dependent pathway, in macrophages and microglia in an MDA5-dependent pathway, and in oligodendrocyte cell lines via MDA5-and RIG-I-dependent pathways (23) (24) (25) . Collectively, these results show that coronaviruses use multiple approaches to evade the innate immune response and that the extent and nature of evasion are cell type dependent. The basis of these cell type-specific differences in IFN expression after coronavirus infection is not well understood.