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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

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Abstract

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 β-oxidation with elevated serum acylcarnitine ratios (C16:0+C18:1)/C2. 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 β-oxidation congenitally or posteriorly in the newborn/ suckling periods. Mice genetically lacking of carnitine transporter OCTN2, resulting in carnitine deficiency and impaired β-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 β-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 β-oxidation after influenza virus infection may have implications for human influenza-associated encephalopathy.

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Authors and Affiliations

  1. Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Kuramoto-cho 3-18-15, Tokushima, 770-8503, Japan

    Dengfu Yao, Ye Chen, Mayumi Shiota, Yuushi Okumura, Hiroshi Yamada & Hiroshi Kido

  2. Department of Laboratory Medicine, School of Medicine, The University of Tokushima, Kuramoto-cho 3-18-15, Tokushima, 770-8503, Japan

    Masamichi Kuwajima

  3. Department of Gastroenterology, Affiliated Hospital, Nantong Medical College, Nantong, 226001, China

    Dengfu Yao

Authors
  1. Dengfu Yao
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  2. Masamichi Kuwajima
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  3. Ye Chen
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  4. Mayumi Shiota
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  5. Yuushi Okumura
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  6. Hiroshi Yamada
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  7. Hiroshi Kido
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Correspondence to Hiroshi Kido.

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Yao, D., Kuwajima, M., Chen, Y. et al. 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. Mol Cell Biochem 299, 85–92 (2007). https://doi.org/10.1007/s11010-005-9046-x

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  • DOI: https://doi.org/10.1007/s11010-005-9046-x

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