臺灣博碩士論文加值系統

以病理學、分子免疫學及微生物學基礎深入探討臺灣以往發生之兩株口蹄疫病毒株O/Taiwan/97及O/Taiwan/99對不同偶蹄類動物之病原性、致病機轉及臨床表徵，得到一些有意義的結果，可作為研擬防疫策略及臨床診斷之參考依據。
SPF 豬人工感染親豬性口蹄疫 O/Taiwan/97病毒，逐日觀察其臨床症狀及病變，臨床症狀包括食慾不振、精神沉鬱等發生在1 DPI (Days post-infection，接種後日數）至7 DPI。病毒血症於1 DPI即出現持續至3 DPI止；於2 DPI時病毒力價最高，其含量為106.33 TCID50/ml。血清中和抗體於4 DPI時出現，21 DPI及301 DPI時血清中和抗體幾何平均值分別為1:861 與1:1097。在1 DPI時，於左前肢之蹠關節上皮可見水泡之產生，2 DPI之水疱液內 FMDV含量為108.63 TCID50/ml。以BHK-21 細胞於1至12 DPI豬隻皮膚組織及2至8 DPI糞便拭子、8 HPI (小時接種後) 95% 豬隻OP fluid 可分離出FMDV，至15 DPI後，豬之上皮組織及臟器皆無法分離出病毒。以RT-PCR 技術於1 DPI至21 DPI於接種處皆可偵測出病毒核酸。於21 DPI時開始再生新蹄，至70 DPI時完全長成。
SPF 豬人工感染親豬性口O/ Taiwan / 97病毒、豬水疱病病毒 (Swine vesicule disease virus)，進行血清生化酵素值的測定。分析及比對標準參考值後發現血中肌酸活酶 (creatine kinase, CK)、乳酸脫氫酶 (lactate dehydrogenase, LDH)、天門冬酸鹽轉氨酶 (aspartate aminotransferase, AST) 與氨基丙酸轉氨酶 (alanine aminotransferase, ALT) 於病毒感染後在統計學上有明顯之變化。結果顯示口蹄疫O/ Taiwan / 97病毒接種豬隻於1 DPI 時ALT即上升，5 DPI 達到高峰後逐漸下降；AST在3 DPI時迅速上升，4、5 DPI達到高峰；CK在4 DPI迅速上升，5 DPI達到高峰；LDH則遲至5 DPI天才上升，6至15 DPI皆維持於高值。豬水疱病毒接種組豬隻之AST、ALT、LDH在感染後其活性微幅上升。可知口蹄疫O/Taiwan /97病毒會導致豬隻四種血清酵素活性上升，此發現應用於病毒早期感染及區別豬口蹄疫與豬水疱病之快速診斷參考數據。
12頭10日齡無口蹄疫抗體之蘭嶼豬 (哺乳仔豬) ，經口感染5 x 108 TCID50 FMD O/Taiwan/97 病毒株，結果感染病毒 6 HPI (Hours post-infection) 後體溫明顯
下降，活力減退，至36 HPI最低降至37.3℃。除一頭耐過存活外，其餘仔豬皆於感染病毒後24 HPI開始陸續死亡，以42 HPI死亡率最高。感染後第12 HPI可於血清中分離到病毒；RT-PCR 檢測結果最早可於感染病毒後第6 HPI於偵測出病毒核酸，感染病毒12 HPI後仔豬之血清生化值LDH及CK值明顯上升。典型虎斑心病變於感染病毒後56 HPI發現，24 HPI死亡之仔豬心肌肉眼無法看出壞死病變，於心肌組織切片下卻有顯著病變，包括心肌 Zenker’s 壞死、心肌細胞橫紋消失、肌細胞質顆粒化及肌細胞核濃縮及破裂等變化。剖檢病變僅見心肌蒼白及肺呈濕重潮紅病變，四肢、嘴及鼻吻部上皮皆正常無水泡病變。應用ISH及IHC 技術，可於感染病毒24 HPI 後死亡仔豬之心肌細胞內偵測到FMDV RNA及抗原，於咽喉,軟顎,氣管,扁桃腺,舌頭,唇,冠狀帶等上皮細胞偵測出FMDV抗原。全身重要要臟器包括上皮組織、心肌等於攻毒後24 HPI皆可以細胞培養方式回收病毒，但攻毒後30、42、48、56及72 HPI死亡仔豬心肌雖有明顯病變，但無法以細胞培養方式回收病毒，其心肌以RT-PCR偵測FMD病毒為陽性。RT-PCR偵測之陽性率較病毒分離率為高。結果亦顯示血清生化值LDH及CK可做為哺乳仔豬感染口蹄疫病毒之早期感染指標。
口蹄疫O/Taiwan/ 99 (O Kimen strain)在黃牛、乳牛、肉羊、乳羊及豬之宿主病原性研究發現：SPF豬感染O/Taiwan/ 99病毒株後會排毒，同居之 SPF豬隻亦會有同樣之症狀；乳牛及山羊接種O/Taiwan/ 99病毒株後可由咽喉食道液 (OP fluid)中回收病毒，另外，山羊也可由肛門拭子回收病毒，攻毒後一週將豬隻移入，同居感染不成立。高劑量O/Taiwan/ 99 (107.3TCID50) 病毒株感染乳牛後一週中和抗體可達512倍，乳牛間同居感染成立；黃牛對O/Taiwan/99病毒株頗具抵抗性，臨床上不會發病但會排毒，黃牛與SPF豬同居感染會導致 SPF豬發病，發病豬隻亦會排出高量病毒。臺灣水牛以舌頭皮內接種口蹄疫O/Taiwan/99 (10 7.59 TCID50/ml) 病毒株後可從肛門拭液、血液、鼻拭液以及食道咽喉液回收口蹄疫病毒，但水牛呈不顯性感染，無臨床症狀亦不感染與其同居飼養之無口蹄疫抗體乳牛和SPF豬隻。

In the study, pathology, microbiology and molecular immunology were applied to study two foot-and-mouth virus strains (FMDV), O/Taiwan/97 and O/Taiwan/99, isolated from epizootics of FMD in Taiwan in 1997 and 1999, respectively. The results including pathogenesis and the mechanism of infection and clinical symptoms in different cloven-hoofed animal species can be applied to develop prevention strategies and clinicalil diagnose FMD.
Specific pathogen free (SPF) pigs were inoculated intradermally at the front-right heel bulb with 0.5 ml of a 106.0 tissue culture infectious dose (TCID50) of FMDV O/Taiwan/97. Symptoms of depression and inappetence appeared at 1 DPI and had subsided by 7 DPI. Vesicles developed in the epidermis of non-inoculated metacarpals joints at 1 DPI, and in the mouth and snout at 2 DPI. Viraemia was detected at 1 DPI and persisted till 3 DPI. The virus was undetectable when the neutralizing antibody (NA) developed at 4 DPI. However, the virus was isolated from the skin from 1 to 12 DPI, from feces from 2 to 8 DPI, and from 95 % oesophageal-pharyngeal (OP) fluid at 8 HPI. No virus was isolated from the skin or visceral organs at 15 DPI and the virus was not detectable from the OP fluid from 12 DPI till 400 DPI. Using a reverse transcriptase-polymerase chain reaction, viral RNA was detected at the inoculation site at 1 DPI till 21 DPI. Neutralizing antibody emerged at 4 DPI and the geometric mean NA titre was 1:861 and 1:1097 at 21 and 301 DPI, respectively. The regrowth of hoof began at 21 DPI; however, remnants of old hoof were still presented at the end of this study. These results suggest monitoring pig’s hooves for residual lesions should be applied to the FMD diagnosis.
The clinical features and the activity of serum enzymes in the pigs infected with the porcinophilic FMDV and SVD were studied. The results showed four enzyme activities released from the damaged muscles, including creatine kinase (CK), lactate dehydronase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) had significant changes in the group of pigs infected with FMDV. On the other hand, in the group of pigs infected with SVDV, the activities of AST, ALT, and LDH were found to be slightly increased. Thus, we suggest early and differential diagnosis of FMD and SVD can be accomplished by measuring the activities of CK, LDH, AST, and ALT.
On the other hand, when the suckling piglets borne by a sow free from antibodies to FMDV were infected intra-orally with the viral suspension containing 5 × 10 8.0 TCID50/ml. The piglets started to die from 24 HPI and only one piglet survived until the end of this experiment. The activities of LDH and CK rose significantly at 12 HPI. Generally, typical “tiger heart” lesions were found in the piglets at 56 HPI, but were not visible in those died by 24 HPI. The virus was recovered from the visceral organs and epithelial tissues of the piglets died after 30 HPI. Using ISH and IHC, the viral RNA and specific FMD antigens were localized within the myocytes and epithelium cells of the piglets. Nevertheless, the virus was recovered from one piglet that died at 24 HPI. The virus coult not be isolated from the piglets died at 30, 42, 48, 56, and 72 HPI with prominent myocardial lesions. The results shown the activities of LDH and CK may serve as early indicators of FMD infection in piglets. This study also provided details of the pathogenesis of FMD in suckling piglets.
In order to study the pathogenicity of O/Taiwan/99 strain (O Kimen strain) of FMDV, the virus was inoculated into healthy cloven-hoofed livestocks reared in Taiwan. Transmission of the virus among the same species of animal or between different species of animal by contact exposure was also studied. In pigs, vesicle formations in the skin were noted, and the lesions were similar to those induced by pig-adapted FMD virus (O /Taiwan/ 97) in a previous study. The infection was transmitted to the cohabitaing pigs. In dairy goats, the virus was isolated from feces and oesophageal-pharyngeal fluid (OPF). In dairy cows, a high dose of the virus, 107.3 TCID50/ml, induced vesicle formations in the muzzle and feet, and serum neutralizing antibody titer was 1: 512 at 7 DPI. The infection was transmitted to the contact-exposed mate. In Taiwan yellow cattle, virus was isolated from feces and infection was transmitted to cohabitant pigs. In steers, the virus was isolated from OPF. In Taiwan buffalo, there were not typical clinical symptoms, and the virus was isolated from feceal swab, blood, nasal swab and OPF. However, cows and pigs were not infected in cohabitation.

中文摘要 i
SUMMARY iii
Contents v
List of Tables x
List of Figures xi
Chapter 1 Introduction 1
1.1 前言 2
Chapter 2 Literature Review 5
2.1 An overview 5
2.2 The virus 5
2.2.1 Virus structure 6
2.2.2 Virus survival 6
2.2.3 Infectious cycle 7
2.3 The disease 7
2.4 History of research in FMD 8
2.5 Transmission 9
2.6 Epidemiology 10
2.7 Clinical signs 11
2.8 Pathology 12
2.9 Pathogenesis 13
2.10 FMD eradication and status in Taiwan 16
2.10.1 Foot and Mouth Disease Situation (BAPHIQ OIE country report) 16
2.10.2 History 17
2.10.3 The FMD outbreak situation in 1997 17
2.10.4 The first case of FMD in ruminants 17
2.10.5 The recent outbreaks of FMD in pigs 20
Chapter 3 Pathology and Viral Distributions of the Porcinophilic Foot-and-Mouth Disease Virus Strain (O/Taiwan/97) in Experimentally Infected Pigs 22
3.1 Introduction 22
3.2 Materials and Methods 25
3.2.1 Experimental animals 25
3.2.2 Virus 25
3.2.3 Infectivity trial 26
3.2.4 Histopathology 26
3.2.5 Cells and virus isolation 27
3.2.6 Immunofluorescent staining 27
3.2.7 Serum neutralization test 28
3.2.8 Reverse transcriptase-polymerase chain reaction 29
3.3 Results 30
3.3.1 Clinical observations 30
3.3.2 Gross findings in infected pigs 30
3.3.3 Histopathologic changes 32
3.3.4 Virus isolation 33
3.3.5 FMDV detection using RT-PCR technique 33
3.3.6 Serum neutralization 34
3.3.7 Immunofluorescence assay 34
3. 4 Discussion 34
Chapter 4 Clinical Features and the Activity of Serum Enzymes in the Pigs Infected with the Porcinophilic Foot-and-Mouth Disease Virus and Swine Vesicular Disease Virus 46
4.1 Introduction 46
4.2 Materials and Methods 48
4.2.1 Experimental animals and virus used 48
4.2.2 Pathological observation: 49
4.2.3 Serum sample collections: 49
4.2.4 Examination of the activity of serum enzymes 50
4.2.5 Data statistics and analysis 50
4.3 Results 50
4.3.1 Clinical features and histopathological changes 50
4.3.2 Changes in white blood cells 52
4.3.3 Activity of serum enzymes 52
4.4 Discussion 54
Chapter 5 Pathology and Clinical Findings of Suckling Piglets Infected with Porcinophilic Foot- and-Mouth Disease (O/Taiwan/97) Virus Strain 67
5.1 Introduction 67
5.2 Materials and Methods 68
5.2.1 Animals 68
5.2.2 Virus 68
5.2.3 Histopathology 69
5.2.4 Reverse transcriptase-polymerase chain reaction 69
5.2.5 Cells and virus isolation 70
5.2.6 Serum Enzyme Activity Examination 70
5.2.7 Statistics and Analyzers 71
5.2.8 Probe preparation and labeling 71
5.2.9 In situ hybridization of tissue sections 71
5.2.10 Immunohistochemistry (IHC) method 72
5.2. 11 Ultrastructural Changes 73
5.3 Results 73
5.3.1 Clinical Signs 73
5.3.2 Gross Lesions 74
5.3.3 Histopathological findings 74
5.3.4 Ultrastructural Changes 74
5.3.5 Serum Enzymes Activities 75
5.3.6 Virus Isolation 76
5.3.7 RT-PCR 76
5.3.8 In situ hybridization (ISH) and IHC 76
5.3.9 Pathogenesis in suckling piglets of FMDV 77
5.4 Discussion 77
Chapter 6 Pathogenic characteristics of the serotype O Taiwan 1999 isolate of foot-and-mouth disease virus in pigs, cattle, Taiwan yellow cattle, Taiwan water buffalo and goats 91
6.1 Introduction 91
6.2 Materials and methods 92
6.2.1 Experimental animals 92
6.2.2 Cell cultures and viruses 93
6.2.3 Serum neutralization test 94
6.2.4 Histopathology 94
6.2.5 Probe preparation and labeling 94
6.2.6 In situ hybridization of tissue sections 95
6.3 Results 96
6.3.1 Experiment 1 96
6.3.2 Experiment 2 96
6.3.3 Experiment　3 98
6.3.4 Experiment　4 98
6.3.5 Experiment 5 98
6.4 Discussion 99
Chapter 7 Conclusion 107
7.1 Conclusion 107
7.2 結論 109
References 112

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