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Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model

View Article: PubMed Central - PubMed

ABSTRACT

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

No MeSH data available.


Related in: MedlinePlus

Effect of iminosugars on blood cytokine levels at necropsy.Following infection with EBOV and treatment IV TID with 1850 mg/kg/day NB-DNJ, 120 mg/kg/day MON-DNJ or water placebo until euthanised (day 9 or 10 for all animals except one in the NB-DNJ treatment group which survived until day 14), blood taken at necropsy was analysed for (A) TNFα, (B) TGFβ and (C) IL-12 mRNA levels by qRT-PCR. Specific cytokine mRNA levels were normalised to β2 microglobulin RNA level and plotted as individual animals with a bar for mean relative gene expression within each group (2–4 animals per group). There were no significant differences between the effects of either of the treatments and the placebo (1-way ANOVA, p = 0.05).
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pone.0167018.g004: Effect of iminosugars on blood cytokine levels at necropsy.Following infection with EBOV and treatment IV TID with 1850 mg/kg/day NB-DNJ, 120 mg/kg/day MON-DNJ or water placebo until euthanised (day 9 or 10 for all animals except one in the NB-DNJ treatment group which survived until day 14), blood taken at necropsy was analysed for (A) TNFα, (B) TGFβ and (C) IL-12 mRNA levels by qRT-PCR. Specific cytokine mRNA levels were normalised to β2 microglobulin RNA level and plotted as individual animals with a bar for mean relative gene expression within each group (2–4 animals per group). There were no significant differences between the effects of either of the treatments and the placebo (1-way ANOVA, p = 0.05).

Mentions: Blood taken at necropsy was assayed by qRT-PCR for guinea pig cytokine mRNA levels to determine whether iminosugar treatment resulted in any impact on the immune response to EBOV. Detectable mRNA was only measured for TNFα, TGFβ and IL-12 and no significant differences were observed between iminosugar-treated and untreated groups (Fig 4). No IFNγ, IL-17, IL-2 or IL-5 mRNA was detected in any of the necropsy samples (data not shown).


Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model
Effect of iminosugars on blood cytokine levels at necropsy.Following infection with EBOV and treatment IV TID with 1850 mg/kg/day NB-DNJ, 120 mg/kg/day MON-DNJ or water placebo until euthanised (day 9 or 10 for all animals except one in the NB-DNJ treatment group which survived until day 14), blood taken at necropsy was analysed for (A) TNFα, (B) TGFβ and (C) IL-12 mRNA levels by qRT-PCR. Specific cytokine mRNA levels were normalised to β2 microglobulin RNA level and plotted as individual animals with a bar for mean relative gene expression within each group (2–4 animals per group). There were no significant differences between the effects of either of the treatments and the placebo (1-way ANOVA, p = 0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120828&req=5

pone.0167018.g004: Effect of iminosugars on blood cytokine levels at necropsy.Following infection with EBOV and treatment IV TID with 1850 mg/kg/day NB-DNJ, 120 mg/kg/day MON-DNJ or water placebo until euthanised (day 9 or 10 for all animals except one in the NB-DNJ treatment group which survived until day 14), blood taken at necropsy was analysed for (A) TNFα, (B) TGFβ and (C) IL-12 mRNA levels by qRT-PCR. Specific cytokine mRNA levels were normalised to β2 microglobulin RNA level and plotted as individual animals with a bar for mean relative gene expression within each group (2–4 animals per group). There were no significant differences between the effects of either of the treatments and the placebo (1-way ANOVA, p = 0.05).
Mentions: Blood taken at necropsy was assayed by qRT-PCR for guinea pig cytokine mRNA levels to determine whether iminosugar treatment resulted in any impact on the immune response to EBOV. Detectable mRNA was only measured for TNFα, TGFβ and IL-12 and no significant differences were observed between iminosugar-treated and untreated groups (Fig 4). No IFNγ, IL-17, IL-2 or IL-5 mRNA was detected in any of the necropsy samples (data not shown).

View Article: PubMed Central - PubMed

ABSTRACT

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

No MeSH data available.


Related in: MedlinePlus