H5N1亚型高致病性禽流感病毒对哺乳动物模型小鼠的致病力研究
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摘要
H5N1亚型高致病性禽流感病毒(HPAIV)是严重威胁社会公共卫生安全的人兽共患病病原。自1997年香港首次发生人感染H5N1亚型高致病性禽流感(HPAI)以来,世界各地不断有人因感染高致病性禽流感病毒而发生死亡的报道。2004年,袭击我国及东南亚国家的H5N1禽流感给世界的养禽业造成了巨大的损失,并对人类的公共卫生造成了极大的影响。2005年我国青海湖地区大批迁徙的野鸟因感染HPAIV而死亡,从而打破了人们认为野鸟带毒排毒而不发病死亡的传统认识。目前H5N1亚型HPAIV已在全球十几个国家有感染人的报道,其致死率超过60%,对人类的健康构成了极大的威胁。HPAIV对哺乳动物的致病力研究,是流感病毒研究领域中的一项十分紧迫和重大的课题。
为了模拟人感染禽流感病毒后的发病进程,本研究以低剂量青海野鸟H5N1高致病性禽流感病毒A/bar-headed goose/Qinghai/3/05 (BHG/3/05)对6周龄的雌性BALB/c小鼠进行感染,建立了H5N1禽流感病毒低剂量感染小鼠发病模型。研究结果显示,低剂量的禽流感病毒感染后,小鼠的发病进程与以往采用高剂量禽流感感染小鼠的发病进程有很大的差异。
在已经建立的小剂量禽流感病毒感染小鼠发病模型的基础上,采用10~1EID_(50)的剂量比较H5N1高致病性人源禽流感病毒A/Anhui/2/05 (AH/2/05)和高致病性禽源流感病毒A/Sichuan/81/05(SC/81/05)在小鼠模型上的致病力差异。AH/2/05感染后小鼠出现体重下降、精神沉郁、食欲减退和神经症状; SC/81/05感染小鼠后,小鼠无任何明显的症状,体重、食欲、精神状态均不受影响。攻毒后的3, 5, 7, 10, 14天取小鼠的脏器在鸡胚上滴定。结果发现,AH/2/05感染后不同的时间病毒在小鼠的各个脏器分布有很大的差异,病毒在小鼠体内的存活时间可以长达14天。通过病理组织切片和免疫组化分析发现,病毒存在于小鼠的脏器细胞并且对小鼠的脏器组织产生了严重的损害。SC/81/05感染后病毒仅在小鼠的鼻甲和肺脏中复制,并且仅可在感染后的第3天能够分离到病毒。通过病理切片和免疫组化观察,病毒没有对组织脏器造成明显的病理变化。本研究的结果证实即使低剂量的H5N1亚型高致病性禽流感病毒仍然能够感染并致死小鼠,并且发现病毒在小鼠体内的存活时间可以长达14天。本研究结果为探讨人禽流感的病理发生机制提供了具有价值的模型,同时为进一步分析H5N1亚型高致病性禽流感病毒在哺乳动物上的致病机制提供了一定的参考价值。
H5N1 subtype highly pathogenic avian influenza viruses (HPAIV) are pathogens of zoonosis that have seriously threaten the public safety. Since the first case that human infected the HPAIV (H5N1) in Hongkong in 1997, the reports about HPAIV infected human beings and caused human dead are never ceased. In 2004, the desease of HPAI in China and eastern-south Asia led to enormous ecnomiclly loss and had influenced the people’s confidence in the poultry. In 2005, thousands of wild birds infected the HPAIV (H5N1) and died, which updated people’s traditional understanding that the HPAIV can now kill the wild birds. Since now, more than ten countries have reported that the HPAIV infected human beings, the mortality over 60%. The pathogenesis of HPAIV in mammals is an urgent and important tissue in the influenza virus research.
To mimic the natural infection of H5N1 avian influenza virus (AIV) in animals, BALB/c mice were inoculated with a low-dosage (10~(0.4) EID_(50)) of H5N1 AIV A/bar-headed goose/3/05 (BHG/3/05). The results demonstrated that progress of diseases had great diversity between high dose infection and low dose infection.
After that we used 10~1EID_(50) of the human H5N1 influenza viruses A/Anhui/2/05 (AH/2/05) and avian H5N1 influenza virus A/Sichuan/81/05 (SC/81/05) to inoculate the BALB/c mice. After infection with the AH/2/05, the mice showed significant disease symptom, including bodyweight descent and symptom neurosis. However, there was no disease symptom and death in the mice after infection with SC/81/05. We isolated the organs and tissues of the infected mice after inoculation at day 3,5,7,10,14 to determine the replication ability of the viruses by eggs. The results showed that the replication ability of the AH/2/05 virus was different at each tissue, and the virus can replicate in mice for more than 14 days. We can detect serios lesions of the tissues through the pathological examination. The SC/81/05 virus was only limited in the turbinate and lung, and can be detected only at day 3 post inoculation without apparent lesions in the tissues. These results are useful for a better understanding of the pathogenesis of H5N1 influenza virus infection in nature.
为了模拟人感染禽流感病毒后的发病进程,本研究以低剂量青海野鸟H5N1高致病性禽流感病毒A/bar-headed goose/Qinghai/3/05 (BHG/3/05)对6周龄的雌性BALB/c小鼠进行感染,建立了H5N1禽流感病毒低剂量感染小鼠发病模型。研究结果显示,低剂量的禽流感病毒感染后,小鼠的发病进程与以往采用高剂量禽流感感染小鼠的发病进程有很大的差异。
在已经建立的小剂量禽流感病毒感染小鼠发病模型的基础上,采用10~1EID_(50)的剂量比较H5N1高致病性人源禽流感病毒A/Anhui/2/05 (AH/2/05)和高致病性禽源流感病毒A/Sichuan/81/05(SC/81/05)在小鼠模型上的致病力差异。AH/2/05感染后小鼠出现体重下降、精神沉郁、食欲减退和神经症状; SC/81/05感染小鼠后,小鼠无任何明显的症状,体重、食欲、精神状态均不受影响。攻毒后的3, 5, 7, 10, 14天取小鼠的脏器在鸡胚上滴定。结果发现,AH/2/05感染后不同的时间病毒在小鼠的各个脏器分布有很大的差异,病毒在小鼠体内的存活时间可以长达14天。通过病理组织切片和免疫组化分析发现,病毒存在于小鼠的脏器细胞并且对小鼠的脏器组织产生了严重的损害。SC/81/05感染后病毒仅在小鼠的鼻甲和肺脏中复制,并且仅可在感染后的第3天能够分离到病毒。通过病理切片和免疫组化观察,病毒没有对组织脏器造成明显的病理变化。本研究的结果证实即使低剂量的H5N1亚型高致病性禽流感病毒仍然能够感染并致死小鼠,并且发现病毒在小鼠体内的存活时间可以长达14天。本研究结果为探讨人禽流感的病理发生机制提供了具有价值的模型,同时为进一步分析H5N1亚型高致病性禽流感病毒在哺乳动物上的致病机制提供了一定的参考价值。
H5N1 subtype highly pathogenic avian influenza viruses (HPAIV) are pathogens of zoonosis that have seriously threaten the public safety. Since the first case that human infected the HPAIV (H5N1) in Hongkong in 1997, the reports about HPAIV infected human beings and caused human dead are never ceased. In 2004, the desease of HPAI in China and eastern-south Asia led to enormous ecnomiclly loss and had influenced the people’s confidence in the poultry. In 2005, thousands of wild birds infected the HPAIV (H5N1) and died, which updated people’s traditional understanding that the HPAIV can now kill the wild birds. Since now, more than ten countries have reported that the HPAIV infected human beings, the mortality over 60%. The pathogenesis of HPAIV in mammals is an urgent and important tissue in the influenza virus research.
To mimic the natural infection of H5N1 avian influenza virus (AIV) in animals, BALB/c mice were inoculated with a low-dosage (10~(0.4) EID_(50)) of H5N1 AIV A/bar-headed goose/3/05 (BHG/3/05). The results demonstrated that progress of diseases had great diversity between high dose infection and low dose infection.
After that we used 10~1EID_(50) of the human H5N1 influenza viruses A/Anhui/2/05 (AH/2/05) and avian H5N1 influenza virus A/Sichuan/81/05 (SC/81/05) to inoculate the BALB/c mice. After infection with the AH/2/05, the mice showed significant disease symptom, including bodyweight descent and symptom neurosis. However, there was no disease symptom and death in the mice after infection with SC/81/05. We isolated the organs and tissues of the infected mice after inoculation at day 3,5,7,10,14 to determine the replication ability of the viruses by eggs. The results showed that the replication ability of the AH/2/05 virus was different at each tissue, and the virus can replicate in mice for more than 14 days. We can detect serios lesions of the tissues through the pathological examination. The SC/81/05 virus was only limited in the turbinate and lung, and can be detected only at day 3 post inoculation without apparent lesions in the tissues. These results are useful for a better understanding of the pathogenesis of H5N1 influenza virus infection in nature.
引文
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121.钟功勋PB1和PA基因与H5N1亚型流感病毒对哺乳动物的致病性有关,中国农业科学院.博士论文
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