Virus-Intrinsic Differences and Heterogeneous IRF3 Activation Influence IFN-Independent Antiviral Protection

Type 1 interferon (IFN) plays a critical role in early antiviral defense and priming of adaptive immunity by signaling upregulation of host antiviral IFN-stimulated genes (ISGs). Certain stimuli trigger strong activation of IFN regulatory factor 3 (IRF3) and direct upregulation of ISGs in addition to IFN. It remains unclear why some stimuli are stronger activators of IRF3 and how this leads to IFN-independent antiviral protection. We found that UV-inactivated human cytomegalovirus (HCMV) particles triggered an IFN-independent ISG signature that was absent in cells infected with UV-inactivated Sendai virus particles. HCMV particles triggered mostly uniform activation of IRF3 and low-level IFN-beta production within the population while SeV particles triggered a small fraction of cells producing abundant IFN-beta. These findings suggest that population-level activation of IRF3 and antiviral protection emerges from a diversity of responses occurring simultaneously in single cells. Moreover, this occurs in the absence of virus replication.