Oropouche virus causes acute hepatitis in mice controlled by Type I interferons

Area of Science:

• Virology
• Hepatology
• Immunology

Background:

• Oropouche virus (OROV), endemic to South America, is a growing public health concern due to a recent outbreak with increased severe manifestations.
• The liver's role in OROV pathogenesis, including acute hepatitis in mild cases and severe coagulopathy in fatal cases, has been historically underrecognized.

Purpose of the Study:

• To establish and characterize mouse models of Oropouche virus-induced hepatic disease to study pathogenesis.
• To compare the pathogenicity of contemporary and historical OROV isolates in a lethal mouse model.
• To provide tools for preclinical evaluation of OROV therapeutics and vaccines.

Main Methods:

• Development of two distinct mouse models for OROV hepatic disease: a lethal model and a self-resolving acute hepatitis model.
• Utilizing a Type I interferon receptor antagonist to induce severe hepatic necrosis in the lethal model.
• Comparative analysis of a contemporary OROV isolate against a historical prototypical strain in the lethal mouse model.

Main Results:

• The lethal mouse model recapitulates severe coagulopathy observed in fatal human OROV cases.
• The sublethal model mirrors mild Oropouche fever with self-resolving acute hepatitis.
• Focal hepatic necrosis progresses to massive necrosis and death when the Type I interferon receptor is antagonized.
• A contemporary OROV isolate demonstrated reduced pathogenicity compared to a historical strain in the lethal mouse model.

Conclusions:

• The developed mouse models effectively represent distinct OROV hepatic disease outcomes in humans.
• These models are crucial for understanding OROV pathogenesis and for the preclinical assessment of interventions.
• Findings suggest potential differences in pathogenicity between circulating and historical OROV strains, warranting further investigation.