臺灣博碩士論文加值系統

魚類野田病毒(Nodavirus)是正意單股RNA病毒，是造成養殖魚類病毒性神經壞死症(VNN)的病原體，在宿主細胞內複製時，會產生雙股核糖核甘酸(dsRNA)的中間產物。野田病毒會誘發宿主細胞先天性免疫反應，然而，目前未知石斑魚黑色素瘤分化相關抗原5(MDA-5)是否和其在哺乳類系統中有一樣角色，即擔任辨認雙股RNA之受體並引發先天性免疫反應。本研究中，使用dsRNA類似物Poly I:C來模擬RNA病毒在細胞內複製時產生的雙股RNA中間產物，並以對NNV具有感受性的石斑魚腦部細胞株(cGB cell)作為測試轉染Poly I:C的研究系統。結果顯示，Poly I:C轉染cGB細胞可以刺激MDA-5、IRF-3、IRF-7及Mx基因表現，並造成粒線體過氧化物(mROS)和自噬體(autophagosome)表現量顯著上升。一旦MDA-5被siRNA先行抑制，轉染Poly I:C後的Mx基因表現以及細胞自噬體和mROS都顯著性下降，證明Poly I:C可以透過活化MDA-5路徑引發第一型干擾素、細胞自噬作用以及mROS的產生。當cGB細胞先處理mROS促進劑Rotenone，然後轉染Poly I:C，Mx基因表現量會比只轉染Poly I:C組高3倍，因此認為mROS也許有協同Poly I:C之作用去加強Mx基因表現。單單處理Rotenone造成細胞自噬體量上升，說明mROS的上升可刺激細胞自噬體的表現；當細胞先處理mROS抑制劑然後轉染Poly I:C，細胞自噬體表現量下降。當以5 mM 3-MA抑制細胞自噬體的形成，則mROS表現量會顯著上升，因此推測，細胞自噬體可能經由清除損壞粒線體來降低mROS量。本研究是第一篇在魚類細胞株中證明MDA-5可以擔任雙股RNA之辨認受體，並且mROS量升高時可以協同Poly I:C增強第一型干擾素之表現，以及細胞自噬作用可以降低mROS在細胞內的累積量達到負回饋調控。

Fish nodavirus, the causative agent of viral nervous necrosis (VNN) of cultured marine fish, is a positive-sense single-stranded RNA virus, and will produce d.s.RNA intermediate during its replication. Fish nodavirus can stimulate innate immune responses in host cells; however, it is still unknown if melanoma different-associated protein 5 (MDA-5) can act as a d.s.RNA recognition receptor and activate intracellular innate immunity in grouper as its role in mammalian cells. In this study, poly I:C was used as an analog of viral d.s.RNA intermediate, and was transfected into a grouper brain cell line cGB which is susceptible to nervous necrosis virus. The results indicated that Poly I:C transfection could stimulate the expression of MDA-5, IRF3, IRF7 and Mx genes, and significantly increased the levels of mitochondrial oxidative substance (mROS) and autophagosomes. When MDA-5 was pre-downregulated by siRNA, the levels of Mx gene expression, mROS and autophagosomes stimulated by Poly I:C transfection all significantly decreased, indicating that d.s. RNA can induce type I interferon response, mROS and autophagy through activating MDA-5 pathway. When cGB cells were pretreated with mROS enhancer rotenone and then transfected with Poly I:C, Mx gene expression level became 3 folds higher than that in only Poly I:C-transfected cells. It is thus suggested that high mROS may synergetically enhance Poly I:C-induced Mx gene expression. Rotenone alone could upregulate autophagosome level in the treated cells, revealing that increasing of mROS could stimulate the formation of autophagosomes. When cGB cells were pretreated with mROS inhibitor and then transfected with Poly I:C, the autophagosome level decreased; furthermore, when the formation of autophagosome was inhibited by 5 mM 3MA, mROS level significantly increased, suggesting that autophagosomes may remove damaged mitochondria and downregulate mROS. This is the first report to demonstrate that MDA-5 could act as a d.s.RNA recognition receptor in fish cell line, and high mROS could synergetically enhance the Poly I:C-induced type I IFN response, and autophagy exhibited negative feedback regulation of mROS.

致謝.................................................................................................................................i
中文摘要........................................................................................................................ii
英文摘要.......................................................................................................................iv
目錄...............................................................................................................................vi
圖目錄...........................................................................................................................ix

第一章 文獻回顧..........................................................................................................1
1. 魚類的免疫系統..............................................................................................1
1.1 免疫系統簡介...........................................................................................1
1.2 魚類的免疫系統發育...............................................................................1
2. 魚類的先天性免疫系統..................................................................................2
2.1 模式辨認受體..........................................................................................2
2.2 干擾素......................................................................................................3
2.3第一型干擾素的訊息傳遞路徑...............................................................4
2.4干擾素刺激基因及抗病毒蛋白...............................................................4
3. 細胞自噬作用....................................................................................................6
3.1 細胞自噬作用介紹..................................................................................6
3.2 細胞自噬體的引發..................................................................................7
3.3 細胞自噬體作用與病毒........................................................................7
4. 活性氧類...........................................................................................................8
4.1 活性氧與氧化壓力介紹............................................................................8
4.2 活性氧的清除............................................................................................9
4.3 活性氧與抗病毒免疫................................................................................9
5. 研究動機........................................................................................................10
第二章 材料與方法....................................................................................................12
1. 細胞株...............................................................................................................12
2. Poly I:C轉染對MDA-5及其下游基因表現之影響........................................12
3. 以siRNA抑制MDA-5基因表現.....................................................................12
4. 抑制MDA-5基因對Mx基因表現之影響......................................................13
5. 抑制MDA-5基因對mROS量的影響............................................................13
6. 抑制MDA-5基因對細胞自噬體表現量的影響.............................................14
7. mROS抑制劑NAC及促進劑Rotenone對Mx基因表現之影響...................14
8. mROS抑制劑NAC及促進劑Rotenone對細胞自噬體表現量之影響.......14
9. 抑制細胞自噬體對mROS表現量之影響.......................................................15
10. RNA萃取以及反轉錄(Reverse transcription).................................................15
11. 即時聚合酶連鎖反應 (Real-time PCR)..........................................................16
12. 測細胞自噬體的免疫螢光染色法...................................................................16
13. 偵測mROS之MitoSOX螢光染色法..............................................................17
第三章 實驗結果........................................................................................................18
1. Poly I:C轉染會誘發MDA-5路徑及第一型干擾素反應..............................18
2. 抑制MDA-5表現對Mx基因表現之影響......................................................18
3. 抑制MDA-5表現對粒線體活性氧(mROS)的影響......................................19
4. 抑制MDA-5表現對細胞自噬體的影響.......................................................19
5. 粒線體活性氧(mROS)會促進Mx基因表現.................................................20
6. Poly I:C 誘發自噬體可受到mROS的調控.................................................21
7. 抑制細胞自噬體對細胞粒線體活性氧(mROS)的影響..............................22
第四章 討論................................................................................................................24
1. cGB細胞中的MDA5是重要的雙股RNA模式辨認受體....................................24
2. cGB細胞中的粒線體過氧化物會促進Mx基因大量表現..............................26
3. cGB細胞中的粒線體過氧化物會促進細胞自噬體生成.............................27
4. cGB細胞自噬體會抑制粒線體過氧化物的產生.........................................29
5. 總結................................................................................................................30

第五章 參考資料........................................................................................................31














圖目錄

圖 1、Poly I:C轉染對cGB細胞MDA-5，IRF-3，IRF-7及Mx基因表現之影響........47
圖2、測試siRNA抑制MDA-5基因表現的效率...........................................................48
圖3、MDA-5基因受抑制對Poly I:C 誘發Mx基因表現之影響.................................49
圖4、MDA-5受抑制對Poly I:C誘發之mROS量的影響.............................................50
圖5、cGB細胞會透過MDA-5作用產生細胞自噬體…...............................................51
圖6、抑制及促進mROS量對Poly I:C誘發Mx基因表現量之影響…........................52
圖7、抑制或促進mROS對細胞自噬體表現量的影響.................................................53
圖8、抑制或促進mROS對Poly I:C誘發細胞自噬體表現量之影響..........................54
圖9、抑制細胞自噬體形成對mROS量之影響.............................................................55
圖10、雙股RNA對cGB細胞MDA-5反應相互調控關係圖.......................................56
表1、Real-time PCR所使用的引子(primer)序列及siRNA序列..................................57
附圖 1、 人類病毒誘發RLR家族的MDA-5 路徑訊息傳遞圖.................................58
附圖 2、細胞免疫螢光染色呈像圖...............................................................................59
附圖 3、 mROS與先天性免疫反應..............................................................................60

陳子翔 (2014)。鹽度對龍膽石斑先天免疫、鈉鉀氯共轉運蛋白及神經壞死病毒
複製之影響。國立台灣大學動物學研究所碩士論文。
王任翔 (2009)。魚類神經壞死症病毒與細胞自噬的交互作用機制。國立台灣大
學動物學研究所碩士論文。
A.M., C., J.F., D. (1996) A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273, 501-503.
Ablasser, A., Bauernfeind, F., Hartmann, G., Latz, E., Fitzgerald, K.A., Hornung, V. (2009) RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol 10, 1065-1072.
Akira, S., Uematsu, S., Takeuchi, O. (2006) Pathogen Recognition and Innate Immunity. Cell 124, 783-801.
Allam, R., Lichtnekert, J., Moll, A.G., Taubitz, A., Vielhauer, V., Anders, H.-J. (2009) Viral RNA and DNA Trigger Common Antiviral Responses in Mesangial Cells. Journal of the American Society of Nephrology : JASN 20, 1986-1996.
Altman, B.J., Rathmell, J.C. (2012) Metabolic Stress in Autophagy and Cell Death Pathways. Cold Spring Harbor perspectives in biology 4, a008763-a008763.
Altmann, S.M., Mellon, M.T., Distel, D.L., Kim, C.H. (2003) Molecular and Functional Analysis of an Interferon Gene from the Zebrafish, Danio rerio. Journal of Virology 77, 1992-2002.
Altmann, S.M., Mellon, M.T., Johnson, M.C., Paw, B.H., Trede, N.S., Zon, L.I., Kim, C.H. (2004) Cloning and characterization of an Mx gene and its corresponding promoter from the zebrafish, Danio rerio. Developmental & Comparative Immunology 28, 295-306.
Anand, S.K., Tikoo, S.K. (2013) Viruses as Modulators of Mitochondrial Functions. Advances in Virology 2013, 738794.
Arad, M., Seidman, C.E., Seidman, J.G. (2007) AMP-Activated Protein Kinase in the Heart: Role During Health and Disease. Circulation Research 100, 474-488.
Azad, M.B., Chen, Y., Gibson, S.B. (2009) Regulation of Autophagy by Reactive Oxygen Species (ROS): Implications for Cancer Progression and Treatment. Antioxidants & Redox Signaling 11, 777-790.
Barlan, A.U., Griffin, T.M., Mcguire, K.A., Wiethoff, C.M. (2011) Adenovirus Membrane Penetration Activates the NLRP3 Inflammasome. Journal of Virology 85, 146-155.
Bell, J.K., Askins, J., Hall, P.R., Davies, D.R., Segal, D.M. (2006) The dsRNA binding site of human Toll-like receptor 3. Proceedings of the National Academy of Sciences 103, 8792-8797.
Berkova, Z., Crawford, S.E., Trugnan, G., Yoshimori, T., Morris, A.P., Estes, M.K. (2006) Rotavirus NSP4 Induces a Novel Vesicular Compartment Regulated by Calcium and Associated with Viroplasms. Journal of Virology 80, 6061-6071.
Bernales, S., McDonald, K.L., Walter, P. (2006) Autophagy Counterbalances Endoplasmic Reticulum Expansion during the Unfolded Protein Response. PLoS Biology 4, e423.
Boo, K.-H., Yang, J.-S. (2010) Intrinsic Cellular Defenses against Virus Infection by Antiviral Type I Interferon. Yonsei Medical Journal 51, 9-17.
Boveris, A., Chance, B. (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochemical Journal 134, 707-716.
Cabiscol, E., Piulats, E., Echave, P., Herrero, E., Ros, J. (2000) Oxidative Stress Promotes Specific Protein Damage inSaccharomyces cerevisiae. Journal of Biological Chemistry 275, 27393-27398.
Canty, T.G., Boyle, E.M., Farr, A., Morgan, E.N., Verrier, E.D., Pohlman, T.H. (1999) Oxidative Stress Induces NF-κB Nuclear Translocation Without Degradation of IκBα. Circulation 100, II-361-Ii-364.
Chang, C.-W., Su, Y.-C., Her, G.-M., Ken, C.-F., Hong, J.-R. (2011) Betanodavirus Induces Oxidative Stress-Mediated Cell Death That Prevented by Anti-Oxidants and Zfcatalase in Fish Cells. PLoS ONE 6, e25853.
Chelikani, P., Fita, I., Loewen, P.C. (2004) Diversity of structures and properties among catalases. Cellular and Molecular Life Sciences CMLS 61, 192-208.
Chen, Y.-M., Su, Y.-L., Lin, J.H.-Y., Yang, H.-L., Chen, T.-Y. (2006) Cloning of an orange-spotted grouper (Epinephelus coioides) Mx cDNA and characterisation of its expression in response to nodavirus. Fish & Shellfish Immunology 20, 58-71.
Chen, Y.-M., Su, Y.-L., Shie, P.-S., Huang, S.-L., Yang, H.-L., Chen, T.-Y. (2008) Grouper Mx confers resistance to nodavirus and interacts with coat protein. Developmental & Comparative Immunology 32, 825-836.
Chiang, H.-L., Terlecky, S.R., Plant, C.P., Dice, J.F. (1989) A Rolefora 70-KilodatonHeatShockProteinin Lysosomal Degradation of Intracellular Proteins. Science 246, 382-385.
Cooke, M.S., Evans, M.D., Dizdaroglu, M., Lunec, J. (2003) Oxidative DNA damage: mechanisms, mutation, and disease. The FASEB Journal 17, 1195-1214.
Cuervo, A.M., Dice, J.F. (2000) Regulation of Lamp2a Levels in the Lysosomal Membrane. Traffic 1, 570-583.
De Leo, A., Arena, G., Lacanna, E., Oliviero, G., Colavita, F., Mattia, E. (2012) Resveratrol inhibits Epstein Barr Virus lytic cycle in Burkitt’s lymphoma cells by affecting multiple molecular targets. Antiviral Research 96, 196-202.
Devasagayam, T., Tilak, J., Boloor, K., Sane, K.S., Ghaskadbi, S.S., Lele, R. (2004) Free radicals and antioxidants in human health: current status and future prospects. J Assoc Physicians India 52, 794-804.
Diebold, S.S. (2008) Recognition of viral single-stranded RNA by Toll-like receptors. Advanced Drug Delivery Reviews 60, 813-823.
E.J., S., H, v.T., N, R., K.W., P. (2001) Non-structural proteins 2 and 3 interact to modify host cell membranes during the formation of the arterivirus replication complex. Jurnal of General Virology 82, 985-994.
Gao, S., von der Malsburg, A., Dick, A., Faelber, K., Schröder, Gunnar F., Haller, O., Kochs, G., Daumke, O. (2011) Structure of Myxovirus Resistance Protein A Reveals Intra- and Intermolecular Domain Interactions Required for the Antiviral Function. Immunity 35, 514-525.
Gosert, R., Kanjanahaluethai, A., Egger, D., Bienz, K., Baker, S.C. (2002) RNA Replication of Mouse Hepatitis Virus Takes Place at Double-Membrane Vesicles. Journal of Virology 76, 3697-3708.
Heydtmann, M. (2009) Macrophages in Hepatitis B and Hepatitis C Virus Infections. Journal of Virology 83, 2796-2802.
Huet, O., Harrois, A., Duranteau, J. (2009) Oxidative Stress and Endothelial Dysfunction during Sepsis. In: Intensive Care Medicine. (Ed. J.-L. Vincent), Springer New York, pp. 59-64.
Hwang, S., Fuji, K., Takano, T., Sakamoto, T., Kondo, H., Hirono, I., Aoki, T. (2011) Linkage Mapping of Toll-Like Receptors (TLRs) in Japanese Flounder, Paralichthys olivaceus. Marine Biotechnology 13, 1086-1091.
Ichimura, Y., Kirisako, T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima, N., Tanida, I., Kominami, E., Ohsumi, M., Noda, T., Ohsumi, Y. (2000) A ubiquitin-like system mediates protein lipidation. Nature 408, 488-492.
Ireland, J.M., Unanue, E.R. (2011) Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. The Journal of Experimental Medicine 208, 2625-2632.
Itoh, S. (2015) Developing Mononuclear Copper–Active-Oxygen Complexes Relevant to Reactive Intermediates of Biological Oxidation Reactions. Accounts of Chemical Research.
Jagannath, C., Lindsey, D.R., Dhandayuthapani, S., Xu, Y., Hunter, R.L., Eissa, N.T. (2009) Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 15, 267-276.
Jensen, V., Robertsen, B. (2004) Cloning of an Mx cDNA from Atlantic Halibut (Hippoglossus hippoglossus) and Characterization of Mx mRNA Expression in Response to Double-Stranded RNA or Infectious Pancreatic Necrosis Virus. Journal of Interferon & Cytokine Research 20, 701-710.
K, T., M, B., S, T., T, N., Y, O. (1992) Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. The Journal of Cell Biology 119, 301-311.
Kanazawa, T., Taneike, I., Akaishi, R., Yoshizawa, F., Furuya, N., Fujimura, S., Kadowaki, M. (2004) Amino Acids and Insulin Control Autophagic Proteolysis through Different Signaling Pathways in Relation to mTOR in Isolated Rat Hepatocytes. Journal of Biological Chemistry 279, 8452-8459.
Kawagoe, T., Sato, S., Matsushita, K., Kato, H., Matsui, K., Kumagai, Y., Saitoh, T., Kawai, T., Takeuchi, O., Akira, S. (2008) Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol 9, 684-691.
Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K.J., Takeuchi, O., Akira, S. (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6, 981-988.
Kihara, A., Kabeya, Y., Ohsumi, Y., Yoshimori, T. (2001) Beclin–phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Reports 2, 330-335.
Kim, H.J., Kim, C.-H., Ryu, J.-H., Kim, M.-J., Park, C.Y., Lee, J.M., Holtzman, M.J., Yoon, J.-H. (2013) Reactive Oxygen Species Induce Antiviral Innate Immune Response through IFN-λ Regulation in Human Nasal Epithelial Cells. American Journal of Respiratory Cell and Molecular Biology 49, 855-865.
Kirkegaard, K., Jackson, W.T. (2005) Topology of Double-Membraned Vesicles and the Opportunity for Non-Lytic Release of Cytoplasm. Autophagy 1, 182-184.
Klionsky, D.J., Emr, S.D. (2000) Autophagy as a Regulated Pathway of Cellular Degradation. Science (New York, N.Y.) 290, 1717-1721.
Kobayashi, K., Inohara, N., Hernandez, L.D., Galan, J.E., Nunez, G., Janeway, C.A., Medzhitov, R., Flavell, R.A. (2002) RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416, 194-199.
Kruzel, M.L., Actor, J.K., Radak, Z., Bacsi, A., Saavedra-Molina, A., Boldogh, I. (2010) Lactoferrin decreases LPS-induced mitochondrial dysfunction in cultured cells and in animal endotoxemia model. Innate immunity 16, 67-79.
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., Mizushima, N. (2004) The role of autophagy during the early neonatal starvation period. Nature 432, 1032-1036.
Kurihara, Y., Kanki, T., Aoki, Y., Hirota, Y., Saigusa, T., Uchiumi, T., Kang, D. (2012) Mitophagy Plays an Essential Role in Reducing Mitochondrial Production of Reactive Oxygen Species and Mutation of Mitochondrial DNA by Maintaining Mitochondrial Quantity and Quality in Yeast. Journal of Biological Chemistry 287, 3265-3272.
Langevin, C., Aleksejeva, E., Passoni, G., Palha, N., Levraud, J.-P., Boudinot, P. (2013) The Antiviral Innate Immune Response in Fish: Evolution and Conservation of the IFN System. Journal of Molecular Biology 425, 4904-4920.
Lee, D.Y., Sugden, B. (2007) The latent membrane protein 1 oncogene modifies B-cell physiology by regulating autophagy. Oncogene 27, 2833-2842.
Lee, J.-Y., Hirono, I., Aoki, T. (2000) Cloning and analysis of expression of Mx cDNA in Japanese flounder, Paralichthys olivaceus. Developmental & Comparative Immunology 24, 407-415.
Li, W.-w., Li, J., Bao, J.-k. (2012) Microautophagy: lesser-known self-eating. Cellular and Molecular Life Sciences 69, 1125-1136.
Lin, C.-H., Christopher John, J.A., Lin, C.-H., Chang, C.-Y. (2006) Inhibition of nervous necrosis virus propagation by fish Mx proteins. Biochemical and Biophysical Research Communications 351, 534-539.
Lin, J.H.-Y., Lin, H.-T., Lopez, C., Chen, T.-Y., Chen, M.-S., Yang, H.-L. (2008) A comparison of the expression of immunity-related rag 1 and ikaros genes with histogenesis of the thymus in Epinephelus malabaricus (Bloch & Schneider). Aquaculture Research 39, 252-262.
Lindenman, J. (1962) Resistance of mice to mouse-adapted influenza A virus. Virology 16, 203–204.
Lum, J.J., DeBerardinis, R.J., Thompson, C.B. (2005) Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6, 439-448.
Mizushima, N., Klionsky, D.J. (2007) Protein Turnover Via Autophagy: Implications for Metabolism. Annual Review of Nutrition 27, 19-40.
Mordier, S., Deval, C., Béchet, D., Tassa, A., Ferrara, M. (2000) Leucine Limitation Induces Autophagy and Activation of Lysosome-dependent Proteolysis in C2C12 Myotubes through a Mammalian Target of Rapamycin-independent Signaling Pathway. Journal of Biological Chemistry 275, 29900-29906.
Mughal, M.S., Manning, M.J. (1985) Antibody responses of young carp, Cyprinus carpio, and grey mullet, Chelon labrosus, immunized with soluble antigen by various routes. In: Fish Immunology. (Eds. M.J. Manning, M.F. Tatner), Academic Press, London/Orlando/San Diego, pp. 313–325.
Nakashima, A., Tanaka, N., Tamai, K., Kyuuma, M., Ishikawa, Y., Sato, H., Yoshimori, T., Saito, S., Sugamura, K. (2006) Survival of parvovirus B19-infected cells by cellular autophagy. Virology 349, 254-263.
Nohl, H., Hegner, D. (1978) European Journal of Biochemistry. 82, 563-567.
Onodera, J., Ohsumi, Y. (2005) Autophagy Is Required for Maintenance of Amino Acid Levels and Protein Synthesis under Nitrogen Starvation*. The Journal of Biological Chemistry 280, 31582-31586.
Ou, M.-C., Chen, Y.-M., Jeng, M.-F., Chu, C.-J., Yang, H.-L., Chen, T.-Y. (2007) Identification of critical residues in nervous necrosis virus B2 for dsRNA-binding and RNAi-inhibiting activity through by bioinformatic analysis and mutagenesis. Biochemical and Biophysical Research Communications 361, 634-640.
Pedersen, K.W., van der Meer, Y., Roos, N., Snijder, E.J. (1999) Open Reading Frame 1a-Encoded Subunits of the Arterivirus Replicase Induce Endoplasmic Reticulum-Derived Double-Membrane Vesicles Which Carry the Viral Replication Complex. Journal of Virology 73, 2016-2026.
Pereiro, P., Dios, S., Boltaña, S., Coll, J., Estepa, A., Mackenzie, S., Novoa, B., Figueras, A. (2014) Transcriptome Profiles Associated to VHSV Infection or DNA Vaccination in Turbot (Scophthalmus maximus). PLoS ONE 9, e104509.
Pestka, S., Krause, C.D., Walter, M.R. (2004) Interferons, interferon-like cytokines, and their receptors. Immunological Reviews 202, 8-32.
Peterhans, E., Grob, M., Burge, T., Zanoni, R. (1987) Virus-Induced Formation of Reactive Oxygen Intermediates in Phagocytic Cells. Free Radical Research 3, 39-46.
Petiot, A., Ogier-Denis, E., Blommaart, E.F.C., Meijer, A.J., Codogno, P. (2000) Distinct Classes of Phosphatidylinositol 3′-Kinases Are Involved in Signaling Pathways That Control Macroautophagy in HT-29 Cells. Journal of Biological Chemistry 275, 992-998.
Pichlmair, A., Schulz, O., Tan, C.-P., Rehwinkel, J., Kato, H., Takeuchi, O., Akira, S., Way, M., Schiavo, G., Reis e Sousa, C. (2009) Activation of MDA5 Requires Higher-Order RNA Structures Generated during Virus Infection. Journal of Virology 83, 10761-10769.
Pösö, A.R., Surmacz, C.A., Mortimore, G.E. (1987) Inhibition of intracellular protein degradation by ethanol in perfused rat liver. Biochemical Journal 242, 459-464.
Prentice, E., Jerome, W.G., Yoshimori, T., Mizushima, N., Denison, M.R. (2004) Coronavirus Replication Complex Formation Utilizes Components of Cellular Autophagy. Journal of Biological Chemistry 279, 10136-10141.
Pua, H.H., Dzhagalov, I., Chuck, M., Mizushima, N., He, Y.-W. (2007) A critical role for the autophagy gene Atg5 in T cell survival and proliferation. The Journal of Experimental Medicine 204, 25-31.
Reikine, S., Nguyen, J.B., Modis, Y. (2014) Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5. Frontiers in Immunology 5, 342.
Remmen, H.V., Ikeno, Y., Hamilton, M., Pahlavani, M., Wolf, N., Thorpe, S.R., Alderson, N.L., Baynes, J.W., Epstein, C.J., Huang, T.-T., Nelson, J., Strong, R., Richardson, A. (2003) Physiological Genomics 16, 29-37.
Robertsen, B., Bergan, V., Røkenes, T., Larsen, R., Albuquerque, A. (2003) Atlantic Salmon Interferon Genes: Cloning, Sequence Analysis, Expression, and Biological Activity. Journal of Interferon & Cytokine Research 23(10), 601-612.
Robertsen, B., Trobridge, G., Leongt, J.-A. (1997) Molecular cloning of double-stranded RNA inducible MX genes from atlantic salmon (Salmo salar l.). Developmental & Comparative Immunology 21, 397-412.
Saito, T., Hirai, R., Loo, Y.-M., Owen, D., Johnson, C.L., Sinha, S.C., Akira, S., Fujita, T., Gale, M. (2007) Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proceedings of the National Academy of Sciences 104, 582-587.
Samuel, C.E. (2001) Antiviral Actions of Interferons. Clinical Microbiology Reviews 14, 778-809.
Sandrock, M., Frese, M., Haller, O., Kochs, G. (2004) Interferon-Induced Rat Mx Proteins Confer Resistance to Rift Valley Fever Virus and Other Arthropod-Borne Viruses. Journal of Interferon & Cytokine Research 21, 663-668.
Sanjuan, M.A., Dillon, C.P., Tait, S.W.G., Moshiach, S., Dorsey, F., Connell, S., Komatsu, M., Tanaka, K., Cleveland, J.L., Withoff, S., Green, D.R. (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253-1257.
Sarbassov, D.D., Ali, S.M., Sabatini, D.M. (2005) Growing roles for the mTOR pathway. Current Opinion in Cell Biology 17, 596-603.
Satoh, T., Kato, H., Kumagai, Y., Yoneyama, M., Sato, S., Matsushita, K., Tsujimura, T., Fujita, T., Akira, S., Takeuchi, O. (2010) LGP2 is a positive regulator of RIG-I– and MDA5-mediated antiviral responses. Proceedings of the National Academy of Sciences 107, 1512-1517.
Scapigliati, G., Romano, N., Buonocore, F., Picchietti, S., Baldassini, M.R., Prugnoli, D., Galice, A., Meloni, S., Secombes, C.J., Mazzini, M., Abelli, L. (2002) The immune system of sea bass, Dicentrarchus labrax, reared in aquaculture. Developmental & Comparative Immunology 26, 151-160.
Scherz-Shouval, R., Elazar, Z. (2007) ROS, mitochondria and the regulation of autophagy. Trends in Cell Biology 17, 422-427.
Schwarz, K.B. (1996) Oxidative stress during viral infection: A review. Free Radical Biology and Medicine 21, 641-649.
Shishido, S.N., Varahan, S., Yuan, K., Li, X., Fleming, S.D. (2012) Humoral innate immune response and disease. Clinical Immunology 144, 142-158.
Simon, H.U., Haj-Yehia, A., Levi-Schaffer, F. (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5, 415-418.
Sir, D., Liang, C., Chen, W.-l., Jung, J.U., Ou, J.-h.J. (2008) Perturbation of autophagic pathway by hepatitis C virus. Autophagy 4, 830-831.
Slavikova, M., Schmeisser, H., Kontsekova, E., Mateička, F., Borecky, L., Kontsek, P. (2003) Incidence of Autoantibodies Against Type I and Type II Interferons in a Cohort of Systemic Lupus Erythematosus Patients in Slovakia. Journal of Interferon & Cytokine Research 23(3), 143-147.
Soucy-Faulkner, A., Mukawera, E., Fink, K., Martel, A., Jouan, L., Nzengue, Y., Lamarre, D., Vande Velde, C., Grandvaux, N. (2010) Requirement of NOX2 and Reactive Oxygen Species for Efficient RIG-I-Mediated Antiviral Response through Regulation of MAVS Expression. PLoS Pathogens 6, e1000930.
Starkov, A.A., Fiskum, G., Chinopoulos, C., Lorenzo, B.J., Browne, S.E., Patel, M.S., Beal, M.F. (2004) The Journal of Neuroscience 24, 7779-7788.
Stowe, D.F., Camara, A.K.S. (2009) Mitochondrial Reactive Oxygen Species Production in Excitable Cells: Modulators of Mitochondrial and Cell Function. Antioxidants & Redox Signaling 11, 1373-1414.
Suhy, D.A., Giddings, T.H., Kirkegaard, K. (2000) Remodeling the Endoplasmic Reticulum by Poliovirus Infection and by Individual Viral Proteins: an Autophagy-Like Origin for Virus-Induced Vesicles. Journal of Virology 74, 8953-8965.
Sun, Y., Ito, S., Nishio, N., Tanaka, Y., Chen, N., Isobe, K.-i. (2014) Acrolein induced both pulmonary inflammation and the death of lung epithelial cells. Toxicology Letters 229, 384-392.
Takada, Y., Mukhopadhyay, A., Kundu, G.C., Mahabeleshwar, G.H., Singh, S., Aggarwal, B.B. (2003) Hydrogen Peroxide Activates NF-κB through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of p65: EVIDENCE FOR THE INVOLVEMENT OF IκBα KINASE AND Syk PROTEIN-TYROSINE KINASE. Journal of Biological Chemistry 278, 24233-24241.
Takahasi, K., Yoneyama, M., Nishihori, T., Hirai, R., Kumeta, H., Narita, R., Gale Jr, M., Inagaki, F., Fujita, T. (2008) Nonself RNA-Sensing Mechanism of RIG-I Helicase and Activation of Antiviral Immune Responses. Molecular Cell 29, 428-440.
Takeuchi, O., Akira, S. (2008) MDA5/RIG-I and virus recognition. Current Opinion in Immunology 20, 17-22.
Takeda, K., Akira, S. (2005) Toll-like receptors in innate immunity. International Immunology 17, 1-14.
Tal, M.C., Iwasaki, A. (2009) Autophagic control of RLR signaling. Autophagy 5, 749-750.
Tal, M.C., Sasai, M., Lee, H.K., Yordy, B., Shadel, G.S., Iwasaki, A. (2009) Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proceedings of the National Academy of Sciences 106, 2770-2775.
Tallóczy, Z., Virgin, I.V.H., Levine, B. (2005) PKR-Dependent Xenophagic Degradation of Herpes Simplex Virus Type 1. Autophagy 2, 24-29.
Tang, D., Kang, R., Cheh, C.W., Livesey, K.M., Liang, X., Schapiro, N.E., Benschop, R., Sparvero, L.J., Amoscato, A.A., Tracey, K.J., Zeh, H.J., Lotze, M.T. (2010) HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene 29, 5299-5310.
Tsukada, M., Ohsumi, Y. (1993) Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Letters 333, 169-174.
Turrens, J.F., Boveris, A. (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochemical Journal 191, 421-427.
Uhl, M., Kepp, O., Jusforgues-Saklani, H., Vicencio, J.M., Kroemer, G., Albert, M.L. (2009) Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells. Cell Death Differ 16, 991-1005.
van der Meer, Y., Snijder, E.J., Dobbe, J.C., Schleich, S., Denison, M.R., Spaan, W.J.M., Locker, J.K. (1999) Localization of Mouse Hepatitis Virus Nonstructural Proteins and RNA Synthesis Indicates a Role for Late Endosomes in Viral Replication. Journal of Virology 73, 7641-7657.
Waris, G., Siddiqui, A. (2003) Regulatory mechanisms of viral hepatitis B and C. Journal of Biosciences 28, 311-321.
West, A.P., Shadel, G.S., Ghosh, S. (2011) Mitochondria in innate immune responses. Nat Rev Immunol 11, 389-402.
Wu, Y.-C., Lu, Y.-F., Chi, S.-C. (2010) Anti-viral mechanism of barramundi Mx against betanodavirus involves the inhibition of viral RNA synthesis through the interference of RdRp. Fish & Shellfish Immunology 28, 467-475.
Wu, Y.C., Chi, S.C. (2007) Cloning and analysis of antiviral activity of a barramundi (Lates calcarifer) Mx gene. Fish & Shellfish Immunology 23, 97-108.
Yap, W., Tay, A., Brenner, S., Venkatesh, B. (2003) Molecular cloning of the pufferfish (Takifugu rubripes) Mx gene and functional characterization of its promoter. Immunogenetics 54, 705-713.
Zelko, I.N., Folz, R.J. (2003) Myeloid zinc finger (MZF)-like, Kruppel-like and Ets families of transcription factors determine the cell-specific expression of mouse extracellular superoxide dismutase. Biochemical Journal 369, 375-386.
Zeng, X., Overmeyer, J.H., Maltese, W.A. (2006) Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. Journal of Cell Science 119, 259-270.