豚鼠抗流感病毒相关因子研究及H9N2亚型禽流感病毒致病力分析
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摘要
近年来A型流感病毒(AIV)在中国的频繁暴发给人们的生命健康带来了严重威胁,造成了巨大的经济损失。高致病性流感病毒会导致感染动物体内炎性因子大量升高,由此认为细胞因子风暴是导致动物死亡的主要原因。早期研究证明流感病毒可以在豚鼠体内感染复制,本研究进一步发现病毒感染并不能导致豚鼠机体产生“高细胞因子风暴”,且豚鼠可以在感染后5～7天清除流感病毒,这为我们研究宿主利用先天性免疫应答机制清除流感病毒提供了十分理想的动物模型。本课题共分为两大部分,第一部分主要是利用豚鼠作为模式动物,豚鼠细胞系作为模式细胞,利用H5N1禽流感病毒作为模式病毒研究宿主抵抗流感病毒的先天性免疫决定因子。主要利用iTRAQ定量蛋白质组学方法结合转录水平分析对AIV感染的豚鼠肺脏组织和肺成纤维细胞系进行表达谱分析。在此基础上,对差异表达蛋白进行抗AIV功能的探索,筛选到了抑制流感病毒复制和下调细胞因子的关键蛋白,明确了豚鼠抗炎性反应的关键通路。论文第二部分为了探索低致病H9N2禽流感病毒对人类的致病性,利用恒河猴作为动物模型进行了H9N2流感病毒致病力分析。具体介绍如下：
第一部分：
通过对豚鼠肺脏组织和肺脏成纤维细胞转录水平和蛋白表达谱变化分析,结果表明无论从体内水平(豚鼠肺脏)还是体外水平(豚鼠肺成纤维细胞),豚鼠感染H5N1AIV后都没有高细胞因子的发生。感染豚鼠24小时后引发肺脏65个蛋白表达上调,135个蛋白表达下调。感染72小时后引发肺脏24个蛋白表达上调,39个蛋白表达下调。AIV感染肺脏成纤维细胞12小时后引发61个蛋白表达上调,71个蛋白表达下调。感染24小时后引发51个蛋白表达上调,30个蛋白表达下调。AIV感染后导致豚鼠肺脏和肺成纤维细胞中免疫应答相关基因表达发生变化,这些基因参与IFN途径、细胞凋亡以及补体激活等。这些H5N1AIV感染变化基因可能具有抗病毒作用,也可能具有调节细胞因子的作用。
利用过表达技术和RNAi技术,在体外过表达RIG-I、MVAS、SPA、SPD、GBP-1、 Mx-1、HSP70和HSP90,同时对GBP-1进行RNAi体外抑制该基因表达,探索上述基因的抗AIV活性。结果表明过表达RIG-I和MAVS可明显抑制流感病毒在豚鼠细胞中的复制,Mx-1也具有抑制作用,但效果不如RIG-I和MAVS明显。GBP-1细胞水平过表达可以下调流感病毒诱导的细胞因子,其在协同RIG-I发挥抗AIV作用中发挥重要作用。
通过研究AIV感染后豚鼠体内补体变化情况发现,豚鼠感染AIV后会导致体内补体C3表达量升高。通过药物拮抗豚鼠体内补体后其抗流感病毒能力明显减弱,同时伴随着抑制体内细胞凋亡,显著上调趋化因子IP10的表达量,表明补体可能通过调控体内细胞凋亡进而可以发挥调节细胞因子的作用。
第二部分：
利用非人类灵长类动物——恒河猴作为模式动物进行了H9N2AIV致病性研究,结果表明感染后恒河猴出现双向热和病毒性肺炎,可以从感染猴的鼻洗液和咽拭子中分离出流感病毒,排毒期持续7～9天,组织嗜性和免疫组化结果表明H9N2AIV可以在上呼吸道(鼻甲骨、气管和支气管)和所有的肺叶中复制。通过本次研究表明恒河猴是一种研究H9N2AIV进化和致病力的较为理想的动物模型。
Influenza A viruses are important pathogens that cause acute respiratory diseases and annual epidemics in humans and poultry, which have become serious health and economic concerns in China. Because proinflammatory cytokines are markedly elevated during highly pathogenic avian influenza virus infection, the cytokine storm is hypothesized to be the main cause of mortaily. Previous reports showed the guinea pig is susceptible to influenza virus. Further study showed that the virus failed to induce the cytokine storm in guinea pig, which is easily eliminated5-7dpi. These demonstrate that the guinea pig is a suitable animal model for host defense against influenza virus studies. This study is mainly divided into two parts. The first part is using guinea pigs as model animal, JH4and104C1as model cells, H5N1influenza viruses as model virus. The host factors affect resistant to infection with influenza A virus was evaluated. In this study, two-dimensional liquid chromatography-tandem mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ) labeling approach and Real-time PCR method was used to investigate the dynamic host response induced by H5N1influenza virus in vivo and in vitro. Based on the data from proteomics analysis, we probe the antivirus function of differentially expressed protein and identify the key pathway of anti-inflammatory activity. The second part is to evaluate the pathogenesis of humans to H9N2avian influenza virus (AIV). The pathogenicity analysis of H9N2influenza virus was determined in non-human primates.
Part1:The global differential expressed protein and selected gene expression changes in lungs and JH4cell infected with H5N1AIV were investigated using iTRAQ proteomic approach and quantitative real-time PCR. The results showed that the H5N1AIV wasn't supportive to induce early and sustained inflammatory in vivo and in vitro. Proteomic approach analysis showed that200proteins were significantly differential expression at1dpi, and63proteins changed at3dpi in lungs in response to H5N1AIV infection. In addition, the cell level showed that132proteins were changed at12hpi, and81proteins changed at24hpi in JH4cell. Using gene ontology and KEGG pathways analysis, the results indicate the differentially expressed proteins are mainly involved in interferon pathways, apoptosis and complement activation. The results suggest that the modulated proteins in infected lungs and cells were possibly involved in protective effects and cytokine regulation.
In vitro anti-influenza virus function of RIG-I, MAVS, SPD, SPA, GBP-1, Mx-1, HSP70and HSP90were investigated using overexpression technology. The GBP-1gene was also investigated using RNAi technology. The results showed that protein expression to over-express RIG-I, MAVS and Mx-1gene decreased the titers of AIV in JH4cell and104C1cell. The inhibition ratio of RIG-I and MAVS are more significantly higher than Mx-1. The overexpression of GBP-1reduced the level of cytokine induced by AIV, however, it made antiviral effect by the synergic action of RIG-I.
Complement C3, a member of the complement system of serum proteins, is a major component of the innate immune and inflammatory responses. In this study, we demonstrate that H5N1influenza virus infected guinea pig had increased levels of C3activation byproducts as compared to guinea pig infected with pandemic2009H1N1influenza viruses. Research in CVF-treated guinea pig demonstrated that C3was required for protection from influenza infection, proper viral clearance, and associated with changes in cellular infiltration. Interestingly, Treatment of influenza virus infected guinea pig with CVF, resulted in a reduction of cell apoptosis and robust IP10gene expression. The results suggest that the complement C3may help control an acute inflammatory response by inducing apoptosis.
Part2:Several cases of humans infected with the H9N2avian influenza virus have been described since1999, however, the infectivity and pathogenicity of H9N2in humans is not well defined. A non-human primate model in rhesus macaques was developed to study H9N2virus infections as a means of better understanding the pathogenesis and virulence of this virus, in addition to testing antiviral drugs. Rhesus macaques inoculated with H9N2AIV presented with biphasic fever and viral pneumonia. H9N2was recovered from nasal washes and pharyngeal samples up to days7-9post infection followed by an increase in HI (hemagglutination inhibition) antibody titers. Tissue tropism and immunohistochemistry indicated that H9N2AIV replicated in the upper respiratory tract (turbinate, trachea, and bronchus) and in all lobes of the lung. Our data suggest that rhesus macaques are a suitable animal model to study H9N2influenza virus infections, particularly in the context of viral evolution and pathogenicity.
第一部分：
通过对豚鼠肺脏组织和肺脏成纤维细胞转录水平和蛋白表达谱变化分析,结果表明无论从体内水平(豚鼠肺脏)还是体外水平(豚鼠肺成纤维细胞),豚鼠感染H5N1AIV后都没有高细胞因子的发生。感染豚鼠24小时后引发肺脏65个蛋白表达上调,135个蛋白表达下调。感染72小时后引发肺脏24个蛋白表达上调,39个蛋白表达下调。AIV感染肺脏成纤维细胞12小时后引发61个蛋白表达上调,71个蛋白表达下调。感染24小时后引发51个蛋白表达上调,30个蛋白表达下调。AIV感染后导致豚鼠肺脏和肺成纤维细胞中免疫应答相关基因表达发生变化,这些基因参与IFN途径、细胞凋亡以及补体激活等。这些H5N1AIV感染变化基因可能具有抗病毒作用,也可能具有调节细胞因子的作用。
利用过表达技术和RNAi技术,在体外过表达RIG-I、MVAS、SPA、SPD、GBP-1、 Mx-1、HSP70和HSP90,同时对GBP-1进行RNAi体外抑制该基因表达,探索上述基因的抗AIV活性。结果表明过表达RIG-I和MAVS可明显抑制流感病毒在豚鼠细胞中的复制,Mx-1也具有抑制作用,但效果不如RIG-I和MAVS明显。GBP-1细胞水平过表达可以下调流感病毒诱导的细胞因子,其在协同RIG-I发挥抗AIV作用中发挥重要作用。
通过研究AIV感染后豚鼠体内补体变化情况发现,豚鼠感染AIV后会导致体内补体C3表达量升高。通过药物拮抗豚鼠体内补体后其抗流感病毒能力明显减弱,同时伴随着抑制体内细胞凋亡,显著上调趋化因子IP10的表达量,表明补体可能通过调控体内细胞凋亡进而可以发挥调节细胞因子的作用。
第二部分：
利用非人类灵长类动物——恒河猴作为模式动物进行了H9N2AIV致病性研究,结果表明感染后恒河猴出现双向热和病毒性肺炎,可以从感染猴的鼻洗液和咽拭子中分离出流感病毒,排毒期持续7～9天,组织嗜性和免疫组化结果表明H9N2AIV可以在上呼吸道(鼻甲骨、气管和支气管)和所有的肺叶中复制。通过本次研究表明恒河猴是一种研究H9N2AIV进化和致病力的较为理想的动物模型。
Influenza A viruses are important pathogens that cause acute respiratory diseases and annual epidemics in humans and poultry, which have become serious health and economic concerns in China. Because proinflammatory cytokines are markedly elevated during highly pathogenic avian influenza virus infection, the cytokine storm is hypothesized to be the main cause of mortaily. Previous reports showed the guinea pig is susceptible to influenza virus. Further study showed that the virus failed to induce the cytokine storm in guinea pig, which is easily eliminated5-7dpi. These demonstrate that the guinea pig is a suitable animal model for host defense against influenza virus studies. This study is mainly divided into two parts. The first part is using guinea pigs as model animal, JH4and104C1as model cells, H5N1influenza viruses as model virus. The host factors affect resistant to infection with influenza A virus was evaluated. In this study, two-dimensional liquid chromatography-tandem mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ) labeling approach and Real-time PCR method was used to investigate the dynamic host response induced by H5N1influenza virus in vivo and in vitro. Based on the data from proteomics analysis, we probe the antivirus function of differentially expressed protein and identify the key pathway of anti-inflammatory activity. The second part is to evaluate the pathogenesis of humans to H9N2avian influenza virus (AIV). The pathogenicity analysis of H9N2influenza virus was determined in non-human primates.
Part1:The global differential expressed protein and selected gene expression changes in lungs and JH4cell infected with H5N1AIV were investigated using iTRAQ proteomic approach and quantitative real-time PCR. The results showed that the H5N1AIV wasn't supportive to induce early and sustained inflammatory in vivo and in vitro. Proteomic approach analysis showed that200proteins were significantly differential expression at1dpi, and63proteins changed at3dpi in lungs in response to H5N1AIV infection. In addition, the cell level showed that132proteins were changed at12hpi, and81proteins changed at24hpi in JH4cell. Using gene ontology and KEGG pathways analysis, the results indicate the differentially expressed proteins are mainly involved in interferon pathways, apoptosis and complement activation. The results suggest that the modulated proteins in infected lungs and cells were possibly involved in protective effects and cytokine regulation.
In vitro anti-influenza virus function of RIG-I, MAVS, SPD, SPA, GBP-1, Mx-1, HSP70and HSP90were investigated using overexpression technology. The GBP-1gene was also investigated using RNAi technology. The results showed that protein expression to over-express RIG-I, MAVS and Mx-1gene decreased the titers of AIV in JH4cell and104C1cell. The inhibition ratio of RIG-I and MAVS are more significantly higher than Mx-1. The overexpression of GBP-1reduced the level of cytokine induced by AIV, however, it made antiviral effect by the synergic action of RIG-I.
Complement C3, a member of the complement system of serum proteins, is a major component of the innate immune and inflammatory responses. In this study, we demonstrate that H5N1influenza virus infected guinea pig had increased levels of C3activation byproducts as compared to guinea pig infected with pandemic2009H1N1influenza viruses. Research in CVF-treated guinea pig demonstrated that C3was required for protection from influenza infection, proper viral clearance, and associated with changes in cellular infiltration. Interestingly, Treatment of influenza virus infected guinea pig with CVF, resulted in a reduction of cell apoptosis and robust IP10gene expression. The results suggest that the complement C3may help control an acute inflammatory response by inducing apoptosis.
Part2:Several cases of humans infected with the H9N2avian influenza virus have been described since1999, however, the infectivity and pathogenicity of H9N2in humans is not well defined. A non-human primate model in rhesus macaques was developed to study H9N2virus infections as a means of better understanding the pathogenesis and virulence of this virus, in addition to testing antiviral drugs. Rhesus macaques inoculated with H9N2AIV presented with biphasic fever and viral pneumonia. H9N2was recovered from nasal washes and pharyngeal samples up to days7-9post infection followed by an increase in HI (hemagglutination inhibition) antibody titers. Tissue tropism and immunohistochemistry indicated that H9N2AIV replicated in the upper respiratory tract (turbinate, trachea, and bronchus) and in all lobes of the lung. Our data suggest that rhesus macaques are a suitable animal model to study H9N2influenza virus infections, particularly in the context of viral evolution and pathogenicity.
引文
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