Impaired long-chain fatty acid metabolism in mitochondria causes brain vascular invasion by a non-neurotropic epidemic influenza A virus in the newborn/suckling period: implications for influenza-associated encephalopathy.
The neuropathogenesis of influenza-associated encephalopathy in children and Reye's syndrome remains unclear. A surveillance effort conducted during 2000-2003 in South-West Japan reveals that almost all fatal and handicapped influenza-associated encephalopathy patients exhibit a disorder of mitochondrial beta-oxidation with elevated serum acylcarnitine ratios (C(16:0)+C(18:1))/C(2). Here we show invasion by a non-neurotropic epidemic influenza A H3N2 virus in cerebral capillaries with progressive brain edema after intranasal infection of mice having impaired mitochondrial beta-oxidation congenitally or posteriorly in the newborn/ suckling periods. Mice genetically lacking of carnitine transporter OCTN2, resulting in carnitine deficiency and impaired beta-oxidation, exhibited significant higher virus-genome numbers in the brain, accumulation of virus antigen exclusively in the cerebral capillaries and increased brain vascular permeability compared to in wild type mice. Mini-plasmin, which proteolytically potentiates influenza virus multiplication in vivo and destroys the blood-brain barrier, accumulated with virus antigen in the brain capillaries of OCTN2-deficient mice but only a little in wild-type mice. These results suggest that the impaired mitochondrial beta-oxidation changes the susceptibility to a non-neurotropic influenza A virus as to multiplication in the brain capillaries and to cause brain edema. These pathological findings in the brain of mice having impaired mitochondrial beta-oxidation after influenza virus infection may have implications for human influenza-associated encephalopathy.
Yao
Dengfu
D
Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Kuramoto-cho 3-18-15, Tokushima, 770-8503, Japan.
Kuwajima
Masamichi
M
Chen
Ye
Y
Shiota
Mayumi
M
Okumura
Yuushi
Y
Yamada
Hiroshi
H
Kido
Hiroshi
H
D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D001483:Base Sequence; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000821:virology; D001927:Brain Diseases / Q000821:virology*; D017931:DNA Primers; D005227:Fatty Acids / Q000378:metabolism*; D007150:Immunohistochemistry; D053122:Influenza A Virus, H3N2 Subtype / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D005227:Fatty Acids