Mechanism of the transmission of highly pathogenic avian influenza virus to humans and the prevention of pandemic

H5N1型高致病性流感病毒（HPAIV）已传播到亚洲、欧洲和非洲的许多国家，不仅感染了大量家禽，而且还感染了越来越多的人，往往具有致命影响。该项目的目的是阐明HPAIV病毒在人体内传播的分子机制，防止人类世界大流行的出现。我们近两年的项目成果总结如下：1。2003年和2005年在中国和越南从人身上分离出的一些HPAIV （H5N1亚型）已经突变为人型，可识别人受体（唾液酸2- 6gal糖链），并可能在人与人之间传播。2. 对抗流感药物达菲（Tamiflu）耐药的HPAIV首次从越南患者中分离得到。我们成功制备了大量的唾液基转移酶（ST6Gal），该酶可合成人流感病毒的Neu5Ac2-6Gal受体。我们还发现高表达ST6Ga1的细胞增强了人流感病毒的感染。4. 182号和192号位点的突变独立地将已知识别禽类受体的H5N1病毒的血凝素（HA）转化为识别人类受体的血凝素。5. 我们发现鸟类和人类的唾液酸2-3(6)半乳糖受体链都存在于鸡和鹌鹑的肠道中，这表明这些动物可能是HPAIV从家禽传播给人类的中间宿主。6. 我们开发了一种简便、灵敏的HPAIV突变检测技术，用于检测禽型向人型的突变，这种突变容易在人与人之间传播，并在人类世界流行。这一方法可能有助于研究HPAIV突变的分子信号，以适应人类。

H5N1 highly pathogenic influenza viruses (HPAIV) have spread to numerous countries in Asia, Europe and Africa infecting not only large numbers of poultry, but also an increasing number of humans, often with lethal effects. The aim of this project is to elucidate the molecular mechanism of transmission of HPAIV into humans and to prevent the emerging of pandemic in human world. The results of our project in last 2 years are summarized as follows: 1. Some of the HPAIV (H5N1 subtype) isolated from humans in China and Vietnam in 2003 and 2005 has already mutated into human type which recognize human receptor (sialic acid2-6Gal sugar chains), and may be able to transmit from human to human. 2. Tamiflu (anti-influenza drug)-resist HPAIV has been firstly isolated from the Vietnam patient who treated with prophylactic dose of Tamiflu. 3. We succeeded to prepare high amount of sialyltransferase (ST6Gal) which make Neu5Ac2-6Gal receptor for human influenza viruses. We also found that the cells highly expressed ST6Ga1 enhanced the infection of human influenza viruses. 4. Mutations at position of 182 and 192 independently convert the hemagglutinin (HA) of H5N1 viruses known to recognize the avian receptor to ones that recognize the human receptor. 5. We found that both bird and human receptor, Sialic acid 2-3(6)Gal sugar chains are present in the chicken and quail intestines, indicating that these animals may have a role as the intermediate hosts for the transmission of HPAIV from poultry to humans. 6. We developed the simple and sensitive technique to detect the mutation of HPAIV from bird type to human type which spread easily from human to human and emerge the pandemic in human world. This method may be useful to survey the molecular signals of HPAIV mutation for the adaptation to humans.