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The influenza B virus mouse model of Reye's syndrome: pathogenesis of the hypoglycaemia
L E Davis1, B M Woodfin, T Q Tran
1Neurology Service, Department of Veterans Affairs Medical Center, Albuquerque, New Mexico 87108.
Insights
Hypoglycemia in Reye's syndrome may stem from influenza B viral liver infection impairing glucose production. This mouse model reveals impaired gluconeogenesis and mitochondrial dysfunction, contributing to encephalopathy.
Area of Science:
- Virology
- Biochemistry
- Pathology
Background:
- Reye's syndrome in children is often associated with hypoglycemia, potentially contributing to encephalopathy.
- Influenza B virus infection is implicated in Reye's syndrome, but its precise role in hypoglycemia pathogenesis is unclear.
Purpose of the Study:
- To investigate the mechanisms of hypoglycemia in a newly developed mouse model of Reye's syndrome.
- To elucidate the role of influenza B virus infection in hepatic glucose metabolism and encephalopathy.
Main Methods:
- Development of a mouse model using intravenous inoculation of influenza B/Lee virus.
- Monitoring of clinical, biochemical, and pathological features, including blood glucose and liver glycogen levels.
- Assessment of gluconeogenesis in liver slices and pyruvate carboxylase localization.
Main Results:
- The mouse model exhibited key features of Reye's syndrome, including hypoglycemia and hepatic glycogen depletion.
- Impaired gluconeogenesis from pyruvate was observed, linked to pyruvate carboxylase mislocalization from mitochondria to the cytosol.
- Reduced brain glucose levels correlated with systemic hypoglycemia.
Conclusions:
- Non-permissive influenza B viral infection of hepatocytes impairs mitochondrial gluconeogenesis, leading to hypoglycemia in the mouse model.
- Hypoglycemia likely contributes to, but does not solely cause, the encephalopathy observed in Reye's syndrome.
- A similar mechanism may underlie hypoglycemia in human Reye's syndrome cases associated with influenza B infection.
Abstract:
Up to 40% of children with Reye's syndrome have hypoglycaemia that could contribute to the patient's encephalopathy. We developed a mouse model in which intravenous inoculation of influenza B/Lee virus produced a non-permissive infection of hepatocytes and cerebral endothelial cells and caused many clinical, biochemical and pathologic features of Reye's syndrome. We used this model to study the pathogenesis of the hypoglycaemia. Beginning 6 hours after virus inoculation and persisting to death 18-30 hours later, blood glucose levels fell by 40% and glycogen disappeared from the liver. Gluconeogenesis in liver slices from a pyruvate substrate was significantly impaired. Pyruvate carboxylase, normally present in hepatocyte mitochondria, was largely displaced into the cytosol, rendering that enzyme fraction relatively useless in the gluconeogenesis pathway. Brain glucose levels fell proportionately to the depressed blood glucose level to a mean of 44 mg/100 g compared to 108 mg/100 g in control brains. We conclude that hypoglycaemia in the mouse model developed largely as a result of a non-permissive influenza viral infection of hepatocytes which impaired the mitochondrial phase of gluconeogenesis. The hypoglycaemia may have contributed to, but did not solely account for, the encephalopathy. A similar non-permissive influenza B infection may cause hypoglycaemia in Reye's syndrome.