Synergistic control of herpes simplex virus pathogenesis by IRF-3, and IRF-7 revealed through non-invasive bioluminescence imaging

Abstract

Interferon regulatory factors IRF-3 and IRF-7 are central to the establishment of the innate antiviral response. This study examines HSV-1 pathogenesis in IRF-3−/−, IRF-7−/− and double-deleted IRF3/7−/− (DKO) mice. Bioluminescence imaging of infection revealed that DKO mice developed visceral infection following corneal inoculation, along with increased viral burdens in all tissues relative to single knockout mice. While all DKO mice synchronously reached endpoint criteria 5 days post infection, the IRF-7−/− mice survived longer, indicating that although IRF-7 is dominant, IRF-3 also plays a role in controlling disease. Higher levels of systemic proinflammatory cytokines were found in IRF7−/− and DKO mice relative to wild-type and IRF-3−/− mice, and IL-6 and G-CSF, indicative of sepsis, were increased in the DKO mice relative to wild-type or single-knockout mice. In addition to controlling viral replication, IRF-3 and −7 therefore play coordinating roles in modulation of inflammation during HSV infection.

Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1

“…Periocular disease scoring was performed as previously described and summarized here: 0, no pathology; 0.5, minor eyelid swelling; 1.0, minor eyelid and nasal swelling; 1.5, moderate eyelid and nasal swelling; 2.0, severe eyelid swelling with minor periocular hair loss and skin damage; 3.0, neurological symptoms (20).…”

“…An additional study showed that STING-deficient mice have increased HSV-1 titers in corneas relative to control mice, but no further parameters of pathogenesis were measured (16). These studies confirm a role for STING in HSV infection and collectively suggest that STING deficiency renders the host highly susceptible to HSV infection, equivalent perhaps to deficiencies in STAT1, type I IFN receptors, or IRF-3/7 (17)(18)(19)(20). These studies notwithstanding, how STING-driven responses shape HSV pathogenesis following peripheral challenge remains unknown.…”

Use of IRF-3 and/or IRF-7 Knockout Mice To Study Viral Pathogenesis: Lessons from a Murine Retrovirus-Induced AIDS Model

“…he type I interferon (IFN) antiviral response (IFN-␣ and IFN-␤) plays a major role in host innate immunity to RNA and DNA virus infections (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). This antiviral type I IFN response is tightly regulated, in part, by interferon regulatory factors (IRFs) via upstream signaling induction by various pattern recognition receptors (PRRs).…”

“…To determine the possible role of IRFs in retroviral pathogenesis, B6 background mouse strains with IRF-3 Ϫ/Ϫ , IRF-7 Ϫ/Ϫ , and DKO congenic status (10,13,35) were infected with 5 ϫ 10 4 PFU of LP-BM5 retrovirus and were compared to MAIDS-susceptible B6 and MAIDS-resistant 129S1/SvImJ (129) mice (NCI, Bethesda, MD) (31,36). Upon sacrifice, at 8 weeks postinfection (wpi), MAIDS was assessed (Fig.…”

“…The inconsistent degrees of B6 genetic background in IRF-3 Ϫ/Ϫ , IRF-7 Ϫ/Ϫ , and DKO mice provide a cautionary note that results seen with these mice, in our studies and in those of others, may not be indicative solely of the knockout of the IRF gene(s) itself. The DKO mice have been bred at least three times independently from the single knockout mice, according to previous reports (3,10,13,15,35), and were previously reported to be of 91% B6 background, versus 97% for the IRF-7 Ϫ/Ϫ mice, via analysis of microsatellite markers (15). These levels of contamination are similar to the B6 background levels observed here by SNP analyses: Ͼ98% in IRF-7 Ϫ/Ϫ , 75% to 85% in IRF-3 Ϫ/Ϫ , and 80% to 90% in DKO mice.…”