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Protease inhibitors prevent the development of human rotavirus-induced diarrhea in suckling mice
Abstract:
Oral inoculation of human rotavirus MO strain (serotype 3) into 5-day-old BALB/c mice caused gastroenteritis characterized by diarrhea (90% on the average, on day 2). Using this animal model, preventive effect of antiviral agents on the development of rotavirus-induced diarrhea was examined. The infectivity of human rotavirus was enhanced by treatment with protease in vitro. A cysteine protease inhibitor, E-64-c, was given orally at 12 hr and 24 hr after MO infection. Oral administration of 0.3 mg of E-64-c decreased the diarrhea ratio to 17.5% on day 2 and to 10% on day 3. Oral administration of 0.15 mg of cysteine protease inhibitor, ovocystatin, completely prevented the diarrhea on day 2. Serine protease inhibitor, aprotinin (0.15 mg x 2), also prevented the diarrhea on day 2 to 14.3%. These protease inhibitors were nontoxic in vitro and to suckling mice. The histopathological changes in the small intestine due to infection recovered 2 days after MO infection in mice treated with E-64-c and ovocystatin. These results suggest that protease inhibitors are protective agents for human rotavirus infection by inhibiting proteases required for viral replication.
Insights
Protease inhibitors like E-64-c, ovocystatin, and aprotinin effectively prevented rotavirus-induced diarrhea in a mouse model. These agents showed no toxicity and aided recovery from intestinal damage, suggesting their potential as antiviral therapies.
Area of Science:
- Virology
- Gastroenterology
- Pharmacology
Background:
- Human rotavirus (serotype 3) causes gastroenteritis, particularly diarrhea, in young children.
- A mouse model using BALB/c mice was developed to study rotavirus infection and test antiviral agents.
- Rotavirus infectivity is enhanced by protease activity, suggesting proteases are crucial for viral replication.
Purpose of the Study:
- To evaluate the preventive effects of protease inhibitors on human rotavirus-induced diarrhea in a mouse model.
- To assess the toxicity and recovery effects of these inhibitors on the host.
Main Methods:
- Oral inoculation of human rotavirus MO strain into 5-day-old BALB/c mice.
- Administration of cysteine protease inhibitors (E-64-c, ovocystatin) and a serine protease inhibitor (aprotinin) at specific time points post-infection.
- Assessment of diarrhea incidence, severity, and histopathological changes in the small intestine.
Main Results:
- Oral E-64-c significantly reduced diarrhea incidence (17.5% on day 2, 10% on day 3).
- Ovocystatin completely prevented diarrhea on day 2.
- Aprotinin reduced diarrhea to 14.3% on day 2.
- Protease inhibitors demonstrated no in vitro or in vivo toxicity and promoted recovery of intestinal histopathology.
Conclusions:
- Protease inhibitors show significant protective effects against human rotavirus infection.
- These findings suggest that inhibiting viral proteases is a viable strategy for developing rotavirus antiviral therapies.
- The tested protease inhibitors are safe and aid in the recovery of rotavirus-induced gastrointestinal damage.
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