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 upgregulating interferon-stimulated genes (ISGs). Certain stimuli trigger strong activation of IFN regulatory factor 3 (IRF3) and direct upregulation of ISGs in addition to IFN. We found that UV-inactivated human cytomegalovirus (HCMV) particles triggered an IFN-independent ISG signature while UV-inactivated Sendai virus (SeV) particles did not. HCMV particles triggered uniform activation of IRF3 and low-level IFN-𝛽 production within the population while SeV particles triggered a small fraction of cells to produce abundant IFN-𝛽. These findings suggest that population level activation of IRF3 and antiviral protection emerges from a diversity of responses occurring simultaneously at a single cell level, even in the absence of virus replication. As disparate virus particles are being developed for multiple clinical uses, understanding the diversity of responses at single cell and population levels is of utmost importance.