急性弓形虫小鼠感染模型的建立与抗动物弓形虫病药物的初步筛选
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摘要
弓形虫病是一种重要的机会致病性人兽共患寄生虫病,能在人和多种哺乳动物之间传播。动物感染后不但会影响生产性能,还将会成为人类弓形虫病的传染源,因此,对该病的防治具有重要的经济学价值和公共卫生学意义。本研究通过建立急性弓形虫小鼠感染模型后,进行抗弓形虫药物的筛选,拟发现用于动物弓形虫病防治的药物,并对有效药物的抗虫机制进行初步研究,为临床上用于治疗动物弓形虫病提供理论依据。
1.弓形虫复苏方法及虫体毒力的摸索及急性弓形虫小鼠感染模型的建立
通过对弓形虫株经不同保存时间及复苏条件后对小鼠致病性的研究,评价虫体保存方法。使用液氮冻存和体内传代法,摸索出了得到毒力稳定的虫体最佳保存时间、复苏代次与接种剂量。在此基础上,确立了急性弓形虫小鼠感染模型:使用本实验室保存半年以内的弓形虫RH虫株速殖子,经小鼠体内传代2次后,腹腔接种超过4 000个虫体/鼠/0.2 mL(KM系、体重20-24 g),将保证所有小鼠在6-10 d内全部死亡。通过模型的建立,为后续弓形虫虫体生物学和药物筛选研究奠定了基础。
2.抗弓形虫病药物筛选的研究
鉴于目前无专用于动物的抗弓形虫病药物,本研究拟通过选用11种已用于抗动物其它原虫病及其病原微生物的药物,来进行抗弓形虫病的研究。发现原用于抗动物球虫病的药物—磺胺氯吡嗪具有很好的抗弓形虫效果,能明显减少弓形虫在小鼠体内的生长、繁殖,可保护50%以上的小鼠免于死亡并长时间存活,并无法检测到虫体。
3.磺胺氯吡嗪对弓形虫速殖子超微结构的影响
弓形虫速殖子经磺胺氯吡嗪溶液处理后,通过扫描电镜与透射电镜观察虫体结构的变化。在扫描电镜下,药物处理后的虫体大小不均,细胞膜凹凸不平、皱缩呈现不完整,部分虫体出现破损、崩解,虫体反光度不均一等。在透射电镜下,药物处理后,部分虫体发生崩解,虫体细胞膜和核膜结构损坏;致密斑颗粒数量明显减少,细胞质发生均质样改变,细胞质中出现许多空泡;细胞核发生异染色质化,染色质边缘与核膜分离并出现空泡;顶端类锥体结构模糊,出现类似多细胞生物的凋亡特征。
4.磺胺氯吡嗪处理前后弓形虫速殖子消减文库的构建
以正常弓形虫速殖子cDNA作为Driver(驱动组),分别以磺胺氯吡嗪、磺胺嘧啶+乙胺嘧啶处理速殖子cDNA作为Tester(实验组),构建了2个消减文库(T1-1、T2-1),经鉴定文库重组率超过85%,片段长度大小不一,均在250~750 bp范围内,后续基因功能分析有待进一步研究。
Toxoplasma gondii is a ubiquitous, apicomplexan parasite of warm-blooded animals, and is one of the most common parasitic infections of humans. It can spread among humans and a variety of mammals. Infected animals will not only affect performance, but also it will become a source of infection human toxoplasmosis. So, prevention and treatment of the disease has important value of economics and public health. This study constructed a model of acute toxoplasmosis in mice infected with Toxoplasma gondii and then screened many drugs. We have found a significant drug (Sulfachloropyrazine). The preliminary mechanism against parasites was studied. It provides a theoretical basis for putting this drug into clinical use. The results are as follows:
Toxoplasma gondii is a ubiquitous, apicomplexan parasite of warm-blooded animals, and is one of the most common parasitic infections of humans. It can spread among humans and a variety of mammals. Infected animals will not only affect performance, but also it will become a source of infection human toxoplasmosis. So, prevention and treatment of the disease has important value of economics and public health. This study constructed a model of acute toxoplasmosis in mice infected with Toxoplasma gondii and then screened many drugs. We have found a significant drug (Sulfachloropyrazine). The preliminary mechanism against parasites was studied. It provides a theoretical basis for putting this drug into clinical use. The results are as follows:
1. Research the preservation method and the virulence of Toxoplasma gondii and construct a model of acute toxoplasmosis in mice
We assess the preservation methords by the pathogenicity in mice infected with toxoplasma gondii being saved and recoveried differently. Using liquid nitrogen freezing and passage method in vivo, we get the optimum way to preserve and the best time for passaging to achieve stable parasite virulence. Then, the acute Toxoplasma gondii infection model in mice has been established: Keeping Toxoplasma gondii tachyzoites in liquid nitrogen within six months and passaging twice in mice, we can get the parasites which can lead all mice infected with at least 4 000 organs die within a week. The model provides the foundation for screening new drugs and researching the biology of parasite.
2. Screening drugs against Toxoplasma gondii
As there are no great anti-toxoplasmosis drugs for animals, tens of drugs which were used as anti-protozoal or other pathogens were chosen against animal toxoplasmosis. A drug Sulfachloropyrazine were found with great efficacy, it can inhibit growth and reproduction of parasites. The survival rate of mice treated with the drug was over 50% and the survivals can live over 2 months.
3. Observe the ultrastructural changes of Toxoplasma gondii tachyzoite dealt with the drug Sulfachloropyrazine.
In the normal group, considerable numbers of viable tachyzoites showed normal features under SEM and TEM. Under the SEM, in the Sulfachloropyrazine group, tachyzoites take outdifferent size, rugged and incomplete cell membrane, some parasites appear damaged and collapsed, with non-uniform reflectivity. Under the TEM, Sulfachloropyrazine group, some parasites collapse, the cell membrane and nuclear membrane structural were damaged, the number of dense granules reduce lowly. The cytoplasmic vacuoles appeared; the nucleus occured heterochromatin and other changes, pyramidal became fuzzy. After all, they appeared similar characteristics of multi-cellular apoptosis.
1.弓形虫复苏方法及虫体毒力的摸索及急性弓形虫小鼠感染模型的建立
通过对弓形虫株经不同保存时间及复苏条件后对小鼠致病性的研究,评价虫体保存方法。使用液氮冻存和体内传代法,摸索出了得到毒力稳定的虫体最佳保存时间、复苏代次与接种剂量。在此基础上,确立了急性弓形虫小鼠感染模型:使用本实验室保存半年以内的弓形虫RH虫株速殖子,经小鼠体内传代2次后,腹腔接种超过4 000个虫体/鼠/0.2 mL(KM系、体重20-24 g),将保证所有小鼠在6-10 d内全部死亡。通过模型的建立,为后续弓形虫虫体生物学和药物筛选研究奠定了基础。
2.抗弓形虫病药物筛选的研究
鉴于目前无专用于动物的抗弓形虫病药物,本研究拟通过选用11种已用于抗动物其它原虫病及其病原微生物的药物,来进行抗弓形虫病的研究。发现原用于抗动物球虫病的药物—磺胺氯吡嗪具有很好的抗弓形虫效果,能明显减少弓形虫在小鼠体内的生长、繁殖,可保护50%以上的小鼠免于死亡并长时间存活,并无法检测到虫体。
3.磺胺氯吡嗪对弓形虫速殖子超微结构的影响
弓形虫速殖子经磺胺氯吡嗪溶液处理后,通过扫描电镜与透射电镜观察虫体结构的变化。在扫描电镜下,药物处理后的虫体大小不均,细胞膜凹凸不平、皱缩呈现不完整,部分虫体出现破损、崩解,虫体反光度不均一等。在透射电镜下,药物处理后,部分虫体发生崩解,虫体细胞膜和核膜结构损坏;致密斑颗粒数量明显减少,细胞质发生均质样改变,细胞质中出现许多空泡;细胞核发生异染色质化,染色质边缘与核膜分离并出现空泡;顶端类锥体结构模糊,出现类似多细胞生物的凋亡特征。
4.磺胺氯吡嗪处理前后弓形虫速殖子消减文库的构建
以正常弓形虫速殖子cDNA作为Driver(驱动组),分别以磺胺氯吡嗪、磺胺嘧啶+乙胺嘧啶处理速殖子cDNA作为Tester(实验组),构建了2个消减文库(T1-1、T2-1),经鉴定文库重组率超过85%,片段长度大小不一,均在250~750 bp范围内,后续基因功能分析有待进一步研究。
Toxoplasma gondii is a ubiquitous, apicomplexan parasite of warm-blooded animals, and is one of the most common parasitic infections of humans. It can spread among humans and a variety of mammals. Infected animals will not only affect performance, but also it will become a source of infection human toxoplasmosis. So, prevention and treatment of the disease has important value of economics and public health. This study constructed a model of acute toxoplasmosis in mice infected with Toxoplasma gondii and then screened many drugs. We have found a significant drug (Sulfachloropyrazine). The preliminary mechanism against parasites was studied. It provides a theoretical basis for putting this drug into clinical use. The results are as follows:
Toxoplasma gondii is a ubiquitous, apicomplexan parasite of warm-blooded animals, and is one of the most common parasitic infections of humans. It can spread among humans and a variety of mammals. Infected animals will not only affect performance, but also it will become a source of infection human toxoplasmosis. So, prevention and treatment of the disease has important value of economics and public health. This study constructed a model of acute toxoplasmosis in mice infected with Toxoplasma gondii and then screened many drugs. We have found a significant drug (Sulfachloropyrazine). The preliminary mechanism against parasites was studied. It provides a theoretical basis for putting this drug into clinical use. The results are as follows:
1. Research the preservation method and the virulence of Toxoplasma gondii and construct a model of acute toxoplasmosis in mice
We assess the preservation methords by the pathogenicity in mice infected with toxoplasma gondii being saved and recoveried differently. Using liquid nitrogen freezing and passage method in vivo, we get the optimum way to preserve and the best time for passaging to achieve stable parasite virulence. Then, the acute Toxoplasma gondii infection model in mice has been established: Keeping Toxoplasma gondii tachyzoites in liquid nitrogen within six months and passaging twice in mice, we can get the parasites which can lead all mice infected with at least 4 000 organs die within a week. The model provides the foundation for screening new drugs and researching the biology of parasite.
2. Screening drugs against Toxoplasma gondii
As there are no great anti-toxoplasmosis drugs for animals, tens of drugs which were used as anti-protozoal or other pathogens were chosen against animal toxoplasmosis. A drug Sulfachloropyrazine were found with great efficacy, it can inhibit growth and reproduction of parasites. The survival rate of mice treated with the drug was over 50% and the survivals can live over 2 months.
3. Observe the ultrastructural changes of Toxoplasma gondii tachyzoite dealt with the drug Sulfachloropyrazine.
In the normal group, considerable numbers of viable tachyzoites showed normal features under SEM and TEM. Under the SEM, in the Sulfachloropyrazine group, tachyzoites take outdifferent size, rugged and incomplete cell membrane, some parasites appear damaged and collapsed, with non-uniform reflectivity. Under the TEM, Sulfachloropyrazine group, some parasites collapse, the cell membrane and nuclear membrane structural were damaged, the number of dense granules reduce lowly. The cytoplasmic vacuoles appeared; the nucleus occured heterochromatin and other changes, pyramidal became fuzzy. After all, they appeared similar characteristics of multi-cellular apoptosis.
引文
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