Blockage of NF-κB activation mitigates disease severity of HSV-1–infected IRF3 R278Q mice. (A) Mice were infected via the ocular route using 2 × 106 PFU/eye in 5 μl. Treatments were initiated on day 3 after infection and administered by i.p. injection once daily until tissue harvest on day 5 or for 7 consecutive days for therapeutic intent. (B–D)Irf3R278Q/R278Q mice (littermates) were infected with HSV-1 and randomized to treatment with 50 mg/kg ACV (n = 17), 10 mg/kg PDTC, (n = 18), ACV + PDTC (n = 16), or saline (n = 18). n = 4 UI controls treated with ACV or PDTC were included. Disease development was followed as % weight change (B) and symptom score (C) until mice reached humane endpoint or full recovery of 100% of starting body weight, represented in (D) survival curve. (E and F) Brain stems from Irf3R278Q/R278Q mice treated with saline (n = 13–14), PDTC (n = 10–14), or ACV (n = 10) were harvested 5 days after infection with HSV-1 and Il6 expression (E), and HSV-1 gB transcripts (F) were analyzed by RT-qPCR and normalized to β-actin (Actb). UI controls were included (n = 3). (G–I)Irf3WT/R278Q heterozygote littermates were infected with HSV-1 and randomized to treatment with 50 mg/kg ACV (n = 13), 10 mg/kg PDTC (n = 15), ACV + PDTC (n = 13), or saline (n = 17). UI controls treated with ACV (n = 4) or PDTC (n = 4) were included. (G) Symptom score. (H) % Weight change. (I) Survival curve. (J–L)Irf3R278Q/R278Q mice (littermates) were infected with HSV-1 and randomized to treatment with 25 mg/kg BMS-345541 (n = 15), 10 mg/kg PDTC, (n = 17), or saline (n = 17). UI controls (n = 4) treated with BMS-345541 were included. Disease development was followed as % weight change (J) and symptom score (K) until mice reached humane endpoint or full recovery of 100% of starting body weight, represented in (L) survival curve. Treatment experiments were independently repeated two times with similar results. Disease development (weight change and symptom score) was compared between the groups using a mixed-effects analysis with Geisser-Greenhouse correction for multiple interacting variables (time and genotype). Error bars; SEM. Survival was analyzed using log-rank Mantel–Cox test. Dead animals were censored in the graphs and thus represented in the graphs with weight and symptom score at time of death. Statistical analyses of gene expression in brain stems (E and F) were analyzed by two-tailed one-way ANOVA for difference of means, followed by an unpaired t test of means, error bars; SD. P values <0.05 were considered statistically significant, *P < 0.05, **P < 0.01, and ***P < 0.001.
Figure 6.

Blockage of NF-κB activation mitigates disease severity of HSV-1–infected IRF3 R278Q mice. (A) Mice were infected via the ocular route using 2 × 106 PFU/eye in 5 μl. Treatments were initiated on day 3 after infection and administered by i.p. injection once daily until tissue harvest on day 5 or for 7 consecutive days for therapeutic intent. (B–D)Irf3R278Q/R278Q mice (littermates) were infected with HSV-1 and randomized to treatment with 50 mg/kg ACV (n = 17), 10 mg/kg PDTC, (n = 18), ACV + PDTC (n = 16), or saline (n = 18). n = 4 UI controls treated with ACV or PDTC were included. Disease development was followed as % weight change (B) and symptom score (C) until mice reached humane endpoint or full recovery of 100% of starting body weight, represented in (D) survival curve. (E and F) Brain stems from Irf3R278Q/R278Q mice treated with saline (n = 13–14), PDTC (n = 10–14), or ACV (n = 10) were harvested 5 days after infection with HSV-1 and Il6 expression (E), and HSV-1 gB transcripts (F) were analyzed by RT-qPCR and normalized to β-actin (Actb). UI controls were included (n = 3). (G–I)Irf3WT/R278Q heterozygote littermates were infected with HSV-1 and randomized to treatment with 50 mg/kg ACV (n = 13), 10 mg/kg PDTC (n = 15), ACV + PDTC (n = 13), or saline (n = 17). UI controls treated with ACV (n = 4) or PDTC (n = 4) were included. (G) Symptom score. (H) % Weight change. (I) Survival curve. (J–L)Irf3R278Q/R278Q mice (littermates) were infected with HSV-1 and randomized to treatment with 25 mg/kg BMS-345541 (n = 15), 10 mg/kg PDTC, (n = 17), or saline (n = 17). UI controls (n = 4) treated with BMS-345541 were included. Disease development was followed as % weight change (J) and symptom score (K) until mice reached humane endpoint or full recovery of 100% of starting body weight, represented in (L) survival curve. Treatment experiments were independently repeated two times with similar results. Disease development (weight change and symptom score) was compared between the groups using a mixed-effects analysis with Geisser-Greenhouse correction for multiple interacting variables (time and genotype). Error bars; SEM. Survival was analyzed using log-rank Mantel–Cox test. Dead animals were censored in the graphs and thus represented in the graphs with weight and symptom score at time of death. Statistical analyses of gene expression in brain stems (E and F) were analyzed by two-tailed one-way ANOVA for difference of means, followed by an unpaired t test of means, error bars; SD. P values <0.05 were considered statistically significant, *P < 0.05, **P < 0.01, and ***P < 0.001.

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