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

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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.


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Histopathological observations in Ebola virus-challenge guinea pigs.(A) Liver, placebo animal 1. Hepatocyte vacuolation and a focus of necrosis (arrow). (B) Liver, placebo animal 1. Hepatocyte necrosis and mineralisation of necrotic cells. (C) Liver, MON-DNJ-treated animal 11. Necrosis and depletion of hepatocytes from around a portal triad. (D) Spleen, MON-DNJ-treated animal 10. Scattered necrotic/apoptotic cells and macrophage-like cells in the red pulp at the interface with the marginal zone.
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pone.0167018.g003: Histopathological observations in Ebola virus-challenge guinea pigs.(A) Liver, placebo animal 1. Hepatocyte vacuolation and a focus of necrosis (arrow). (B) Liver, placebo animal 1. Hepatocyte necrosis and mineralisation of necrotic cells. (C) Liver, MON-DNJ-treated animal 11. Necrosis and depletion of hepatocytes from around a portal triad. (D) Spleen, MON-DNJ-treated animal 10. Scattered necrotic/apoptotic cells and macrophage-like cells in the red pulp at the interface with the marginal zone.

Mentions: Histopathology showed lesions in the liver consisting of abnormal vacuolation of hepatocytes (Fig 3A), foci of necrosis with mild neutrophilic and/or lymphocytic infiltration (Fig 3A), mineralisation (Fig 3B), necrosis and depletion of hepatocytes from around portal triads and increased numbers of mononuclear cells around portal triads (Fig 3C). In the spleen, abnormalities in the red pulp comprised congestion (Fig 3D), a patchy increase in numbers of polymorphs and diffuse infiltration of macrophages. In the white pulp depletion of lymphocytes from peri-arteriolar lymphoid sheaths, scattered single cell necrosis/apoptosis (Fig 3D) and an increase in the numbers of macrophages at the interface with red pulp (Fig 3D). There was a marked absence of lymphoid follicles in the splenic white pulp of all animals.


Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model
Histopathological observations in Ebola virus-challenge guinea pigs.(A) Liver, placebo animal 1. Hepatocyte vacuolation and a focus of necrosis (arrow). (B) Liver, placebo animal 1. Hepatocyte necrosis and mineralisation of necrotic cells. (C) Liver, MON-DNJ-treated animal 11. Necrosis and depletion of hepatocytes from around a portal triad. (D) Spleen, MON-DNJ-treated animal 10. Scattered necrotic/apoptotic cells and macrophage-like cells in the red pulp at the interface with the marginal zone.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5120828&req=5

pone.0167018.g003: Histopathological observations in Ebola virus-challenge guinea pigs.(A) Liver, placebo animal 1. Hepatocyte vacuolation and a focus of necrosis (arrow). (B) Liver, placebo animal 1. Hepatocyte necrosis and mineralisation of necrotic cells. (C) Liver, MON-DNJ-treated animal 11. Necrosis and depletion of hepatocytes from around a portal triad. (D) Spleen, MON-DNJ-treated animal 10. Scattered necrotic/apoptotic cells and macrophage-like cells in the red pulp at the interface with the marginal zone.
Mentions: Histopathology showed lesions in the liver consisting of abnormal vacuolation of hepatocytes (Fig 3A), foci of necrosis with mild neutrophilic and/or lymphocytic infiltration (Fig 3A), mineralisation (Fig 3B), necrosis and depletion of hepatocytes from around portal triads and increased numbers of mononuclear cells around portal triads (Fig 3C). In the spleen, abnormalities in the red pulp comprised congestion (Fig 3D), a patchy increase in numbers of polymorphs and diffuse infiltration of macrophages. In the white pulp depletion of lymphocytes from peri-arteriolar lymphoid sheaths, scattered single cell necrosis/apoptosis (Fig 3D) and an increase in the numbers of macrophages at the interface with red pulp (Fig 3D). There was a marked absence of lymphoid follicles in the splenic white pulp of all animals.

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