FIG 4.
Miglustat treatment of Ifnar1−/− mice with established HAV infection. (A) Experimental design. Groups of female (F) (n = 5 per group) or male (M) (n = 4) mice, infected 5 days previously with mouse-passaged mp6-HM175 virus, were treated with miglustat (50 mg twice daily by gavage) or the sham water control for 3.5 days prior to necropsy. q.d, once a day. (B) Serum ALT on day 5 and at necropsy on day 8. Symbols representing results from mice treated with miglustat are shaded. (C) Intrahepatic HAV RNA at necropsy on day 8. (D) Mean numbers of apoptotic hepatocytes (left) and inflammatory foci (right) per 40× field of view in H&E-stained liver sections. (E) Liver of a miglustat-treated animal showing hepatocytes with multiple small vesicles in the cytoplasm (arrows). (F) Mean number of liver cells staining for cleaved caspase 3 per 20× field of view. (G) Apoptotic hepatocytes staining positively for cleaved caspase 3 in sham (left)- and miglustat (right)-treated mice. (H) Spleen weight at necropsy on day 8. (I) Representative images of H&E-stained splenic sections. (J) Representative images of splenic sections stained immunohistochemically for cleaved caspase 3. (K) Infection-induced changes in intrahepatic cytokine and chemokine mRNA abundances in miglustat- and sham-treated animals. Data shown represent the ΔCT values between cytokine and actin transcripts, with baseline values for each derived from the means of results from 3 to 4 individual uninfected, untreated Ifnar1−/− mice (baseline shown only for Ifng). Statistical testing was done by two-way analysis of variance (ANOVA) with Tukey’s multiple-comparison test (C) or a Mann-Whitney test (D, H, and K).