Assessing IRF3 as a Master Regulator of Acute Hepacivirus Clearance in Mice

Human genetic variation contributes to a wide array of disease outcomes following hepatitis C virus (HCV) infection. However, much of the host genetic variation guiding these disparate outcomes remains unknown. Norway rat hepacivirus (NrHV), a rodent homolog of HCV, can be employed to elucidate host factors driving increased susceptibility to hepacivirus infection. Laboratory strains of mice (such as C57BL/6) are inbred and have defined and consistent genetics over time. To model hepacivirus infection in a genetically diverse population, we employed the Collaborative Cross (CC), an array of genetically diverse mice that model the genetic diversity observed in human populations. We infected a panel of CC mice with NrHV, revealing a gradient of infection outcomes like those observed in humans. We identified a CC line, CC071, that experiences chronic infection of NrHV, whereas C57BL/6 mice experience acute, self-resolving hepatitis (Brown 2024). By breeding susceptible (CC071) and resistant (C57BL/6) mice, we mapped a quantitative trait locus (QTL) on chromosome 7 associated with chronic infection. Harbored within this QTL was a non-functional form of IRF3, a key transcription factor for Type 1 Interferons. Thus, we hypothesized that defects in IRF3 were responsible for CC071 mice’s inability to clear NrHV infection, unlike their C57BL/6 counterparts. To address this hypothesis, we studied NrHV infection in wild-type (WT) C57BL/6 mice and C57BL/6 mice where Irf3 has been knocked out (Irf3-/-). We measured body weight loss, complete blood count, and NrHV viremia over the course of 5 weeks. Ultimately, Irf3-/- mice experienced delayed clearance of NrHV relative to their C57BL/6 counterparts. This suggests that while malfunctional IRF3 plays a role in the induction of chronic infection for CC071 mice, it likely works in conjunction with other affected genes located on chromosome 7. Thus, IRF3 does not serve alone as a master regulator of NrHV clearance in mice.