人呼吸道甲型流感病毒受体的分布和感染H5N1流感病毒的病理变化
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摘要
1.背景和目的
2003年12月至今,H5N1禽流感相继在欧亚和非洲爆发,令人震惊的是到目前为止,WHO证实已造成335人感染,有引起世界性大流感的趋势。目前, H5N1病毒如何跨种属障碍感染人的分子机制仍未完全清楚。禽流感病毒在人感染率极低,同样人流感病毒很难在水禽类复制,其主要原因为受体结合特异性限制,流感病毒通过其表面HA与宿主细胞唾液酸受体特异性结合而感染宿主,绝大多数禽流感病毒与唾液酸α-2,3Gal受体结合,而人流感病毒与唾液酸α-2,6Gal受体结合,相应的禽类和人分别表达唾液酸α-2,3Gal受体和唾液酸α-2,6Gal受体为主。这种受体类型和分布不同被认为流感病毒在禽类和人之间跨种属传递的主要障碍。本研究目的是探讨人呼吸道各年龄组各部位流感病毒受体的分布规律、为H5N1病毒直接感染人提供理论依据以及禽流感病毒H5N1感染人的病理学特点和组织嗜性。
2.方法
2.1亲和组织化学法检测人呼吸道唾液酸α-2,3Gal和α-2,6Gal受体的表达。
2.2人呼吸道组织的流感病毒体外感染。
2.3应用免疫组织化学法,检测和观察人感染高致病禽流感病毒尸体解剖全身各组织器官和人呼吸道组织体外感染流感病毒后病毒抗原的分布。
2.4免疫组化-免疫荧光双染法:免疫组化法单克隆抗体抗SP-A、CD68分别标记II型肺泡细胞和巨噬细胞,免疫荧光染色法抗流感病毒NP单克隆抗体标记流感病毒蛋白NP。
2.5采用普通光学显微镜观察法,对1例人感染高致病禽流感病毒H5N1的系统尸体解剖病例组织标本进行病理学观察。
3.结果
3.1人呼吸道流感病毒受体的分布,唾液酸α-2,6Gal受体在气管、支气管呈高密度分布,随着支气管分级逐渐降低分布减少,至肺泡分布最少;而唾液酸α-2,3Gal受体以呼吸部即呼吸细支气管和肺泡为主,气管、支气管和细支气管少量分布。
3.2胎儿、婴幼儿、儿童青少年和成年人呼吸道唾液酸α-2,3Gal和α-2,6Gal受体的表达无显著性差异。
3.3 14例人标本,呼吸细支气管上皮细胞、肺泡Ⅱ型上皮细胞、肺巨噬细胞均被10株H5N1病毒感染,10株病毒感染无明显差异,而支气管至终末细支气管上皮细胞仅个别细胞感染,气管上皮细胞无感染。
3.4人感染高致病禽流感H5N1病毒各组织器官的病理特点:脱屑性气管支气管炎,肺脏弥漫性肺泡上皮损伤和/或坏死、肺泡间隔淋巴浆细胞浸润和纤维化。肺外器官:肾小管局灶坏死,骨髓细胞少量细胞坏死,中枢神经系统少量细胞变性、坏死,脾脏白髓萎缩、红髓充血,肝细胞脂肪变性,胰腺外分泌部部分腺泡上皮坏死。
3.5 H5N1病毒在各组织器官的分布:肺泡的II型肺泡细胞、巨噬细胞,肾小球系膜细胞,胰腺外分泌部腺泡上皮细胞和骨髓细胞、巨噬细胞流感病毒NP均呈阳性表达,显示出这些细胞为H5N1病毒主要攻击对象。其它胃肠道粘膜腺上皮、肾小管上皮细胞、中枢神经系统细胞、扁桃体巨噬细胞、气管和支气管上皮细胞、骨骼肌细胞、心肌细胞和脾脏的巨噬细胞少量阳性表达。
4.结论
4.1人呼吸道上皮细胞均有流感病毒唾液酸α-2,6Gal和α-2,3Gal受体的分布,以唾液酸α-2,6Gal受体分布为主。气管、支气管唾液酸α-2,6Gal受体呈高密度分布,随着支气管分级逐渐降低分布减少,至肺泡分布最少,而唾液酸α-2,3Gal受体以呼吸部即呼吸细支气管和肺泡为主,气管、支气管和细支气管仅少量分布。同时,人呼吸道发育成熟过程中,唾液酸α-2,3Gal和α-2,6Gal受体的表达无明显变化。
4.2呼吸道组织对H5N1病毒敏感,呼吸细支气管上皮、肺泡Ⅱ型上皮细胞和肺泡巨噬细胞是其攻击的主要靶细胞,细支气管、支气管和气管少量上皮也可感染,支持唾液酸α-2,3Gal受体分布特点。
4.3人气管至肺泡细胞同时表达肺泡唾液酸α-2,6Gal受体和α-2,3Gal受体,同时感染人和禽流感病毒。提示人也是重要流感病毒“基因混合器”,可能有助于病毒重配和形成大流行株的潜能。
4.4 H5N1主要感染下呼吸道表达唾液酸α-2,3Gal受体的细胞,提示高致病禽流感病毒H5N1具有致命性但可能不易发生人传染人。
4.5 H5N1病毒可引起播散性感染,累及全身多组织器官,肺脏是其侵害的最主要靶器官,其次是肾脏、骨髓、胰腺和中枢神经系统等。H5N1病毒在骨髓大量复制,可形成新的感染灶,加重病毒血症和全身各组织器官感染受累及为临床上疑似高致病禽流感病毒感染严重病例应用骨髓穿刺检测H5N1病毒不失为一种新的途径。
1 Background and object
Since 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 Methods
2.1 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 Results
3.1 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 Conclutions
4.1 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.
2003年12月至今,H5N1禽流感相继在欧亚和非洲爆发,令人震惊的是到目前为止,WHO证实已造成335人感染,有引起世界性大流感的趋势。目前, H5N1病毒如何跨种属障碍感染人的分子机制仍未完全清楚。禽流感病毒在人感染率极低,同样人流感病毒很难在水禽类复制,其主要原因为受体结合特异性限制,流感病毒通过其表面HA与宿主细胞唾液酸受体特异性结合而感染宿主,绝大多数禽流感病毒与唾液酸α-2,3Gal受体结合,而人流感病毒与唾液酸α-2,6Gal受体结合,相应的禽类和人分别表达唾液酸α-2,3Gal受体和唾液酸α-2,6Gal受体为主。这种受体类型和分布不同被认为流感病毒在禽类和人之间跨种属传递的主要障碍。本研究目的是探讨人呼吸道各年龄组各部位流感病毒受体的分布规律、为H5N1病毒直接感染人提供理论依据以及禽流感病毒H5N1感染人的病理学特点和组织嗜性。
2.方法
2.1亲和组织化学法检测人呼吸道唾液酸α-2,3Gal和α-2,6Gal受体的表达。
2.2人呼吸道组织的流感病毒体外感染。
2.3应用免疫组织化学法,检测和观察人感染高致病禽流感病毒尸体解剖全身各组织器官和人呼吸道组织体外感染流感病毒后病毒抗原的分布。
2.4免疫组化-免疫荧光双染法:免疫组化法单克隆抗体抗SP-A、CD68分别标记II型肺泡细胞和巨噬细胞,免疫荧光染色法抗流感病毒NP单克隆抗体标记流感病毒蛋白NP。
2.5采用普通光学显微镜观察法,对1例人感染高致病禽流感病毒H5N1的系统尸体解剖病例组织标本进行病理学观察。
3.结果
3.1人呼吸道流感病毒受体的分布,唾液酸α-2,6Gal受体在气管、支气管呈高密度分布,随着支气管分级逐渐降低分布减少,至肺泡分布最少;而唾液酸α-2,3Gal受体以呼吸部即呼吸细支气管和肺泡为主,气管、支气管和细支气管少量分布。
3.2胎儿、婴幼儿、儿童青少年和成年人呼吸道唾液酸α-2,3Gal和α-2,6Gal受体的表达无显著性差异。
3.3 14例人标本,呼吸细支气管上皮细胞、肺泡Ⅱ型上皮细胞、肺巨噬细胞均被10株H5N1病毒感染,10株病毒感染无明显差异,而支气管至终末细支气管上皮细胞仅个别细胞感染,气管上皮细胞无感染。
3.4人感染高致病禽流感H5N1病毒各组织器官的病理特点:脱屑性气管支气管炎,肺脏弥漫性肺泡上皮损伤和/或坏死、肺泡间隔淋巴浆细胞浸润和纤维化。肺外器官:肾小管局灶坏死,骨髓细胞少量细胞坏死,中枢神经系统少量细胞变性、坏死,脾脏白髓萎缩、红髓充血,肝细胞脂肪变性,胰腺外分泌部部分腺泡上皮坏死。
3.5 H5N1病毒在各组织器官的分布:肺泡的II型肺泡细胞、巨噬细胞,肾小球系膜细胞,胰腺外分泌部腺泡上皮细胞和骨髓细胞、巨噬细胞流感病毒NP均呈阳性表达,显示出这些细胞为H5N1病毒主要攻击对象。其它胃肠道粘膜腺上皮、肾小管上皮细胞、中枢神经系统细胞、扁桃体巨噬细胞、气管和支气管上皮细胞、骨骼肌细胞、心肌细胞和脾脏的巨噬细胞少量阳性表达。
4.结论
4.1人呼吸道上皮细胞均有流感病毒唾液酸α-2,6Gal和α-2,3Gal受体的分布,以唾液酸α-2,6Gal受体分布为主。气管、支气管唾液酸α-2,6Gal受体呈高密度分布,随着支气管分级逐渐降低分布减少,至肺泡分布最少,而唾液酸α-2,3Gal受体以呼吸部即呼吸细支气管和肺泡为主,气管、支气管和细支气管仅少量分布。同时,人呼吸道发育成熟过程中,唾液酸α-2,3Gal和α-2,6Gal受体的表达无明显变化。
4.2呼吸道组织对H5N1病毒敏感,呼吸细支气管上皮、肺泡Ⅱ型上皮细胞和肺泡巨噬细胞是其攻击的主要靶细胞,细支气管、支气管和气管少量上皮也可感染,支持唾液酸α-2,3Gal受体分布特点。
4.3人气管至肺泡细胞同时表达肺泡唾液酸α-2,6Gal受体和α-2,3Gal受体,同时感染人和禽流感病毒。提示人也是重要流感病毒“基因混合器”,可能有助于病毒重配和形成大流行株的潜能。
4.4 H5N1主要感染下呼吸道表达唾液酸α-2,3Gal受体的细胞,提示高致病禽流感病毒H5N1具有致命性但可能不易发生人传染人。
4.5 H5N1病毒可引起播散性感染,累及全身多组织器官,肺脏是其侵害的最主要靶器官,其次是肾脏、骨髓、胰腺和中枢神经系统等。H5N1病毒在骨髓大量复制,可形成新的感染灶,加重病毒血症和全身各组织器官感染受累及为临床上疑似高致病禽流感病毒感染严重病例应用骨髓穿刺检测H5N1病毒不失为一种新的途径。
1 Background and object
Since 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 Methods
2.1 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 Results
3.1 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 Conclutions
4.1 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.
引文
[1] Webster RG, Bean WJ, Gorman OT, et al. Evolution and ecology of influenza A virues. Microbiol Rev, 1992; 56: 152-179
[2] Murphy BR, Webster RG. Fields virology. 3rd edition Philadelphia: Lippincott-Raven, 1996;1397-1445
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