Abstract
Infection by hepatitis E virus (HEV) via the oral route causes acute hepatitis. Extra-hepatic manifestations of HEV infection may stem from various causes; however, its distribution in organs such as the liver, as well as the mechanisms underlying HEV-induced cell injury, remain unclear. The objective of this study was to determine the chronological distribution of HEV in various tissues of HEV-challenged miniature pigs and to investigate the mechanisms underlying HEV-induced cell death in the pancreas and liver. Virological and serological analyses were performed on blood and faecal samples. Histopathology of the liver and extra-hepatic tissues was analysed. Cell death pathways and immune cell characterisation in inflammatory lesions were analysed using immunohistochemistry. The liver and pancreas displayed inflammation and cellular injury, and a large amount of HEV was observed in the lesions. The liver was infiltrated by T and natural killer cells. HEV was identified in all organs except the heart, and was associated with immune cells. Although the liver and the pancreas strongly expressed TNF-α and TRAIL, TUNEL assay results were negative. RIP3 and pMLKL were expressed in the pancreas. RIP3, but not pMLKL, was expressed in the liver. Pancreatitis induced in HEV-infected miniature pigs is associated with necroptosis.
Highlights
Worldwide, 14 million symptomatic infections, 5,200 stillbirths, and 300,000 deaths are attributed to hepatitis E virus (HEV) according to the World Health O rganisation[1]
HEV RNA was detected in the plasma, peripheral blood mononuclear cells (PBMCs), and faeces by quantitative reverse transcription PCR (RT-qPCR) (Table 1, Supplementary Table S1)
HEV-specific antibodies were detected in the plasma, indicating that these may be used as an immunological indicator of HEV infection (Fig. 1C)
Summary
14 million symptomatic infections, 5,200 stillbirths, and 300,000 deaths are attributed to hepatitis E virus (HEV) according to the World Health O rganisation[1]. Clinical symptoms of HEV are mainly associated with acute hepatitis, fulminant hepatic failure, or chronic hepatitis in immunocompromised patients and the elderly. Extra-hepatic lesions, including acute pancreatitis, renal failure, neurological diseases, haematological diseases, and the Guillain–Barre syndrome, are linked with HEV infection, cases of which are increasing. 55 patients with hepatitis E in India, Nepal, Poland, and France were diagnosed with moderate to severe acute pancreatitis. The association between other hepatitis virus infections and acute pancreatitis is well known, the presence of HEV in the human. HEV pathogenesis in the pancreas has not been elucidated in animal models or humans. HEV infection occurs in humans from all age groups, but mainly in the elderly, who usually suffer from chronic diseases such as hypercholesterolaemia, diabetes, and hypertension. As the cholesterol pathway is closely associated with infection by enteric viruses, including HEV and norovirus, treatment with statin drugs may enhance the replication of these viruses[17,18,19]
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