| Budget Amount *help |
¥10,600,000 (Direct Cost: ¥10,600,000)
Fiscal Year 2000: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 1999: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Research Abstract |
In south China, the continuous transmission of avian influenza viruses into human population is currently occurring. In our two year's investigation (1999-2000), we found several important mechanisms on the host mediated variation of influenza viruses in Asia.
1) The Hemagglutinin (HA) of H3 human influenza viruses does not support viral replication in duck intestine despite its avian origin. A Leu-to-Gln mutation at position 226 and a Ser-to-Gly mutation at 228 in the HA of human A/Udorn/307/72 (H3N2) permit a reassortant virus to replicate in ducks.
2) Immunofluorescense assays with Neu5Gc2-3Gal-specific antiserum detected this moiety primarily on the crypt epitherial cells of duck colon. Such recognition with biological results suggests that recognition of the Neu5Gc2-3Gal moiety plays an important role in the enterotropism of avian influenza viruses.
3) Epitherial cells in pig trachea has receptor sialosugar chains that binds both of bird and human influenza A viruses (Neu5Ac2-6Gal fo
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r humans aud Neu5Ac2-3Gal for birds). These results indicate that pig may play as a mixing vessel of human and bird influenza viruses in nature. The host range selection of the receptor binding specificity of the A virus hemagglutinin occurrs during the maintenance of the virus in different host cells which express different receptor sialo-sugar chains.
4) Substrate specificity of influenza A virus neuraminidase (receptor destroying enzyme) showed that all viruses had similar specificities for Neu5Ac2-3Gal, while the activities for Neu5Gc2-6Gal ranged marginal, as represented by avian and early N2 human viruses, to high (although only one-third the activity for Neu5Ac2-3Gal), as represented by swine and more recent N2 human viruses. Using site specific mutagenesis, we identified in the earliest human virus with a detectable increase in Neu5Ac2-6Gal specificity a change at position 275 (Leu to Val) that enhanced the specificity for this substrate.
5) An Influenza virus with an HA recognizing Neu5Ac2-6Gal but not Neu5Ac2-3Gal or Neu5Gc2-3Gal failed to replicate in horses. Biochemical and immunohistochemical analyses and a lectin-binding assay demonstrated the abundance of the Neu5Gc2-3Gal moiety in epithelial cells of horse trachea, indicating that recognition of this moiety is critical for viral replication in horses.
The above new results show that the aim of this project is satisfactory progressed, and the fundamental experimantal results to elucidate the mechanism of host range variation and emerging of the new subtype of the hemagglutinin and neuraminidase of influenza viruses in Asia and to establish the fundamental idea for the control of the influenza virus variation. Less
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