摘要
本研究首次用Affymetrix猪全基因组表达谱芯片对猪感染猪瘟病毒(classical swine fever virus,CSFV)前和感染后临床症状明显期外周血白细胞(peripheral blood leucocyte,PBL)中基因表达变化进行了分析,获得了迄今最为完整的CSFV感染猪PBL差异表达基因数据库;在完成对CSFV感染差异基因生物学功能分类后,着重分析了涉及细胞凋亡相关基因功能组,初步推测了CSFV感染白细胞诱导的凋亡基因相互作用网络;在病毒蛋白和宿主相互作用研究方面,阐明了多功能蛋白血红素加氧酶1(heme oxygenase 1,HO-1)和CSFV E2相互作用对PK-15细胞中病毒复制、感染滴度的影响。
课题研究中,利用Affymetrix猪全基因组表达谱芯片分析了感染CSFV后宿主基因表达水平的变化,对CSFV抗体及病毒基因组检测阴性的3头60日龄长白猪颈部肌肉注射104 TCID50/头CSFV石门株血毒,以攻毒前和攻毒后CSF临床症状明显期自体PBL作为对照。提取3头猪攻毒前后白细胞样品总RNA,基因芯片分析转录表达差异。结果表明攻毒前和后样品相比,共筛选到PBL中1745个基因的转录水平上调或下调表达2倍以上。根据这些基因的生物学功能可分为9个功能组:细胞增殖和细胞周期(3.6 %);免疫反应(2.1 %);细胞凋亡(1.4 %);酶和激酶活性(1.4 %);信号转导(1.4 %);转录(0.7 %);受体活性(0.7 %);细胞因子/趋化因子(0.4 %);未知功能基因(88.3 %)。这些表达差异基因的数据为深入研究CSFV感染的致病机理提供了基础。
在掌握了CSFV感染PBL差异基因表达谱的基础上,进一步深入分析了CSFV感染引起猪白细胞凋亡的分子机制。感染猪的PBL中共筛选到24个发生2倍以上变化细胞凋亡相关基因,并随机挑选差异表达的12个白细胞凋亡相关基因用SYBR greenⅠ荧光定量RT-PCR进行了验证。经过对24个基因的功能分析,初步推测了CSFV感染诱导PBL凋亡基因的相互作用网络。CSFV感染诱导的PBL细胞凋亡涉及了线粒体、内质网应激和死亡受体途径。提出CSFV感染猪后诱导的PBL凋亡是一种凋亡和抗凋亡共存在的过程。检测到caspase-3、6和7基因表达变化但未检测到caspase-8,可以说明CSFV感染宿主临床症状明显期细胞凋亡已处于晚期阶段,而非凋亡的启始阶段。另外还有许多重要的凋亡有关蛋白如,组织蛋白酶(Cathepsin)D、B1,MAPKAPK 3(Mitogen-activated protein kinase-activated protein kinase 3),PNAS-5,RPL6,细胞色素P450,HSP27和HSP90等在细胞凋亡中发挥的具体作用需待进一步研究。
在病毒蛋白和宿主相互作用的研究中鉴定了一个新奇的和CSFV E2相互作用、影响病毒复制的宿主蛋白-HO-1。激光共聚焦显微镜分析HO-1和病毒E2蛋白共定位于感染病毒的PK-15细胞质中,聚集在细胞核周围。CSFV感染细胞后HO-1蛋白的表达随感染时间逐渐升高。应用siRNA技术沉默PK-15细胞中HO-1蛋白表达后,细胞中CSFV的复制水平显著降低,细胞内和细胞培养上清中病毒的感染滴度也显著下降。最终鉴定出PK-15细胞模型中HO-1受E2蛋白调控表达。
本研究鉴定的大量差异表达基因体现着CSFV和宿主细胞相互作用的结果,从宿主全基因组表达差异水平反应了CSFV的致病机理,为分阶段、有层次的探索CSFV的致病机理,逐步阐明CSFV感染的分子机制揭开了序幕。
Classical swine fever virus (CSFV) is a small enveloped virus with a positive stranded RNA genome which belongs in the genus Pestivirus, together with two bovine viral diarrhea viruses (BVDV) and border disease virus (BDV), within the family Flaviviridae. The viral genome is approximately 12.5 kb in size and contains a single large open reading frame that encodes a 3,898 amino acid polyprotein. CSFV has a particular tropism for cells of the immune system and is known to cause severe leukopenia, in particular lymphopenia, featuring atrophy of primary lymphoid tissue and bone marrow, and depletion of different subsets of leukocytes (T- and B-lymphocytes, monocytes-macrophages and granulocytes) in infected pigs. All leukocytes are depleted during CSFV infection, but B-lymphocytes are particularly susceptible. Besides the reduction in leukocyte numbers, lymphocyte activation and function during virulent CSFV infection are severely impaired, thereby significantly decreasing antibody production and host defenses. The destruction of leukocytes following CSFV infection is largely associated with apoptosis in thymus, spleen, lymph nodes and bone marrow.
DNA microarray technology, in combination with bioinformatics, has proved to be a very efficient high-throughput tool and offers great advantages in the study of genomic expression profiles of cells. The present study provides the first pan-genomic microarray analysis of pig transcriptional responses to CSFV infection, in which the genomic transcriptional levels of porcine PBL prepared from CSFV-inoculated pigs with severe clinical symptoms were analyzed using the Affymetrix porcine GeneChip. Total RNA was extracted from PBL collected before and after infection. Results showed that expression of 2,919, 2,859 and 2,995 genes from the 3 pigs were altered post-infection, of which altered expression of 2,662 genes was identified in two or three animals and subsequently subjected to one-way ANOVA statistical analysis (p<0.05). In all, 1,745 genes (8.64 % of all genes present in the array) were confirmed as having a greater than twofold altered expression, with 877 up-regulated and 868 down-regulated. Of 877 up-regulated genes, 24.3% (213/877) were found in all three animals, 61.2% (537/877) found up-regulated in two animals while not changed in another, 14.5% (127/877) found up-regulated in two animals while down-regulated in another. Of 868 down-regulated genes, 37.2% (323/868) were found in all three animals, 55.6% (483/868) found down-regulated in two animals while not changed in one, 7.2% (62/868) found down-regulated in two animals while up-regulated in the third. The functions of the 1,745 genes were observed by the Gene Ontology tool, available from the Affymetrix web site. Surprisingly, 88.3 % (1,540/1,745) were not functionally annotated, with only 205 genes (11.7 %) showing clear functional annotation. These clustered into 8 functional groups: cell proliferation and cycle (62/1745; 3.6 %), immune response (37/1745; 2.1 %), protein kinase activity (25/1745; 1.4 %) , apoptosis (24/1745; 1.4 %), signal transduction (24/1745; 1.4 %), transcription (13/1745; 0.7 %), receptor activity (13/1745; 0.7 %), cytokine/ chemokine (7/1745; 0.4 %).
Viral infections are generally associated with numerous changes in host gene expression that determine the fate of the infected cells and the eventual outcome of the viral infection. Molecular pathogenetic studies of viral infection involve the investigation of these specific changes within the host cell or, more completely, within a specific tissue or organ. The blood samples used in the study were collected at day 7 p.i., the most severe phase of the disease. Real time RT-PCR showed that the numbers of gene copies of CSFV replicating in PBL of the infected pigs were 106.03±526 copies 100/ng total RNA (mean±SD), indicating that a high proportion of the leukocytes were infected. A rapid onset of leukopenia was detected with levels of PBL in all 3 infected animals declining from 20,667±1,379 cells/μl before infection to 12,000±1,646 cells/μl at day 4 p.i. This loss of PBL further progressed until day 10 p.i., reaching levels as low as 7,100±1,176 cells/μl. This result confirms the depletion of PBL in the infected pigs. To investigate further loss of lymphocytes - the main target of CSFV during infection - the T-cell subpopulations of the 3 pigs were analyzed by FACS at days 4, 7 and 10. Results showed that the severest depletion of CD3+CD4+ and CD3+CD8+ T-cell subsets (P <0.05) were observed by day 7 p.i. This is consistent with the findings of a previous study, showing that CD3+CD4+ cells and CD3+CD8+ cytotoxic T-cell subsets were strongly influenced by the viral infection. To explore the factors causing leukopenia apoptosis analysis was applied to PBL using the Annexin V: FITC Apoptosis Detection Kit and FACScan flow cytometry and using the manufacturers’protocols. Results clearly showed that apoptosis was observed in PBL from the same blood samples of the 3 pigs used for microarray with the proportion of apoptotic cells in a total of 10,000 leucocytes per test being significantly increased from 7.03 % before infection to 25.56 % (P<0.05) afterwards, while cell death increased correspondingly, from 1.48 % to 6.46 % (P<0.05). This increase in apoptotic PBL is consistent with the observations of a previous study. Analyzed the 24 apoptotic genes showed that the significant differences were observed in cellular apoptosis genes expression post-infection (p.i.) and the network of apoptosis was concluded. This study provided a valuable information for further exploring the molecular mechanism of apoptosis caused by CSFV infection.
In this study we defined Heme oxygenase 1 (HO-1) as a novel CSFV E2 action partner in PK-15 cells. E2 binding was confined to productively infected PK-15. We demonstrate that the CSFV E2 interaction likely occurs at the limiting membranes of late endosomes/multivesicular bodies and that HO-1 depletion is associated with a significant decline in the viral replication and infectivity of released virions; this don’t coincided with the increasing of apoptosis occurred in PK-15 inoculated CSFV compared to contrals. Cumulatively, our data suggest that HO-1 is essential for the proper life cycle of CSFV in target cells.
In conclusion, the present study has described a complete transcriptional response of pigs to CSFV infection. Microarray analysis has shown that expression of 1,745 genes in PBL were altered following CSFV infection, This work has established a most comprehensive differential transcriptional profile of CSFV-infected pigs, although the application of these data to elucidate the viral pathogenesis is still limited. Further functional investigation of the altered genes may facilitate understanding of the pathogenic mechanisms and molecular responses of host cells to CSFV infection.
引文
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