| 1 Background and objectSince December 2003, avian H5N1 influenza viruses currently circulating in poultry in Eurasian and African countries have caused repeated infection in humans, constituting a significant and persistent pandemic threat. So far, 335 WHO-confirmed human cases of the virus infection have been identified. The molecular mechanism of interspecies transmission from avian species to human has still not been fully described. Avian influenza viruses do not efficiently infect humans. Conversely, human viruses replicate poorly in ducks. Host tropism of influenza viruses is restricted by receptor specificity. The binding of Influenza virus to host cell is mediated via the viral surface protein hemaggglutinin(HA), which recognized cell surface sialic acid (SA). HA from human or avian influenza viruses differ in their ability to recognize different receptor structure. Human influenza viruses preferentially bind to the SAα-2,6 Gal, whereas avian viruses prefer the SAα-2,3 Gal, which predominate in their respective target species, these different linkage types and their distribution have been considered as the major barrier for interspecies tansmission between avian species and human. The object in this report is to study the distribution and prevalence of SAα2,3Gal and SAα2,6Gal in the airway epithelia of different anatomical areas of the human respiratory tract of different age groups for providing evidence for transmission from avian to human of H5N1 viruses, and the pathological characteristic and tissue tropism of avian influenza A virus subtype H5N1 in human.2 Methods2.1 The expression of SAα2,3Gal and SAα2,6Gal receptor in tissues of trachea, bronchus, bronchiole and alveolus were detected using lectin histochemical analysis.2.2 The ex vivo infection of freshly-excised human tracheal, bronchial, bronchiolar and pulmonary tissues.2.3 The distribution of influenza virus antigen in the one case of full autopsy tissue samples from the patient with fatal H5N1 influenza and ex vivo influenza viruses-infected tissues of trachea, bronchus, bronchiole and alveolus were analyed by immunohistochemistry. 2.4 Double staining: The monoclonal antibody against surfactant protein A of type II alveolar cell and the monoclonal antibody against CD68 of macrophage with immunohistochemistry, respectively. The monoclonal antibody against NP protein of influenza virus with immunofluorescence were carried on the ex vivo infection of human lung tissues.2.5 Pathological features of 1 case of systematic autopsy tissues from the patient with fatal H5N1 influenza was studied by light microscopy.3 Results3.1 Distribution of SAα2,6Gal was mainly detected in the trachea and bronchus and to a lesser degree in the alveolar cell. In contrast, SAα2,3Gal receptor was more regularly observe in respiratory bronchiole and lung alveolus cells, and only sporadic expression of SAα2,3Gal was observed in trachea, bronchus and bronchiole epithelial cells.3.2 There were no significant difference for SAα2,6Gal andα2,3Gal receptor expression levels in the respiratory tract between antenates, infants, children and adults.3.3 Respiratory bronchiole epithelium cells, TypeⅡpenumonocytes and pulmonary macrophages were infected by all 10 strains in 14 cases of human sample and no difference in infection among 10 strains H5N1 viruses. But only sporadic infection of in bronchus and terminal bronchiole epithelium cells were observed, and trachea was not observed.3.4 Pathological feature of avian influenza A H5N1: Tracheal and bronchial desquamative inflammation. The pulmonary pathology was diffuse alveolar damage and/or necrosis, desquamative pneumonia plus interstitial lymphoplasmacytic infiltration and fibrosis. Pathological change of extrapulmonary organ and tissue, tubular focal necrosis of kidney, some of cells necrosis in bone marrow, The central nervous system (CNS) showed a few of cells degeneration and necrosis. the spleen showed atrophic white pulp and congested red pulp, hepatocyte steatosis, some gland epithelium cell of pars exocrina pancreatic necrosis was noted.3.5 The distribution of H5N1 viruses in all tissues and organs: Immunohistochemistry showed positive monoclonal antibody against NP of influenza virus in alveolar type II pneumocytes and macrophages, glomerular mesangial cells, pars exocrina pancreatic epithelium and various kinds of haemopoietic stem cells and macrophages. Positive reactions of monoclonal antibody against NP of influenza virus was also detected in a few of tracheal and bronchial epithelial cells, intestinal mucosal glandular epithelium, renal tubular epithelial cells, central nervous systemic gliocytes, tonsillar macrophages, skeletal muscle myocytes, cardiocytes , and macrophages in spleen.4 Conclutions4.1 Both SAα2,6Gal and SAα2,3Gal were expressed but SAα2,6Gal predominated in human respiratory tract. Distribution of SAα2,6Gal was mainly detected in the trachea and bronchus and to a lesser degree in the alveolar epithelium. In contrast, SAα2,3Gal receptor was more regularly observe in respiratory bronchiole and lung alveolus cells, and only sporadic expression of SAα2,3Gal was observed in trachea, bronchus and bronchiole epithelial cells. Also, There was no tendency for SAα2,6Gal andα2,3Gal receptor expression levels in the respiratory tract with respiratory system development.4.2 Respiratory tract tissues were susceptible to H5N1 viral infection. Respiratory bronchiole, typeⅡpenumonocyte and alveolar macrophage were the major target cells of H5N1 viral infection in human. Only sporadic infection of in bronchiolar, bronchial, tracheal epitheliums were observed. These supported the distribution of SAα2,3Gal receptor in respiratory tract.4.3 From bronchial epithelium to penumonocyte in human respiratory tract both expressed SAα-2,6Gal and SAα-2,3Gal, and were infected by human and avian viruses. These findings suggest that humans themselves may act as"mixing vessels"to facilitate reassortment events and potential generate an influenza virus with pandemic potential.4.4 H5N1 preferentially infects cells in the lower respiratory tract, where the avian virus receptor is prevalent. The result indicated that the H5N1 avian influenza virus is so lethal to humans but so difficult to spread.4.5 In human, H5N1 virus might cause a disseminated infection and multi-organ damages which were primary and predominant lung, next to kidney, bone marrow, pancreas and CNS and so on.
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