The influenza B virus mouse model of Reye's syndrome: pathogenesis of the hypoglycaemia.
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.
Neurology Service, Department of Veterans Affairs Medical Center, Albuquerque, New Mexico 87108.
L E
LE
Davis
B M
BM
Woodfin
T Q
TQ
Tran
L S
LS
Caskey
J M
JM
Wallace
O U
OU
Scremin
K S
KS
Blisard
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000209:etiology* / Q000382:microbiology; D009981:Influenza B virus; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000473:pathology; D012202:Reye Syndrome / Q000150:complications*
D001786:Blood Glucose; D005947:Glucose