ANIMAL MODEL DEVELOPMENT FOR MICROSPORIDIOSIS:OPPORTUNISTIC INFECTIONS

微孢子虫病动物模型的开发：机会性感染

基本信息

批准号：
6116170
负责人：
Elizabeth Schmidt Didier
金额：
$ 5.31万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2000-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6116170
关键词：
AIDS Mammalia bioimaging /biomedical imaging biotechnology communicable diseases gallbladder immunology inflammation intestines liver lymphatic system microscopy parasitism virus

项目摘要

Microsporidia cause opportunistic infections in persons with AIDS, organ transplant recipients, children, and travelers. Enterocytozoon bieneusi is the most prevalent microsporidian but attempts to establish a tissue culture system for generating organisms has been unsuccessful. The only nonhuman hosts known for E. bieneusi include pigs and nonhuman primates (eg. Macaca mulatta). Ten SIV-infected rhesus macaques were inoculated orally with E. bieneusi harvested from the stool and duodenal lavage aspirates of human AIDS patients. Spores were detected in stools one week later and continued sporadically for approximately two years or until death of the monkeys, but the inconsistency of spore shedding presently renders this model inadequate for testing antimicrosporidial compounds. However, the monkeys did become infected with E. bieneusi and parasite-associated lesions were identified in the gall bladder, liver, and small intestine. Attempts to infect small animals (eg. gerbils, at hymic mice, immunesuppressed mice) with E. bieneusi also have failed to date. Due to the difficulties in establishing a useful animal model for E. bieneusi, a surrogate microsporidian, Vittaforma corneae is presently being used to develop an animal model for testing lead compounds in vivo. Athymic mice developed wasting (cachexia) and ascites and died 15 - 60 days after intraperitoneal inoculation with 5 x 107 - 1 x 104 V. corneae organisms. Athymic mice infected with 1 x 107 V. corneae and treated with fumagillin survived only a few days longer than non-treated mice but there were statistically significantly fewer parasite-associated lesions in the small intestines, gall bladder, and liver of treated mice. Since fumagillin is toxic in mammals, attempts are underway to obtain fumagillin analogues and related compounds for testing against V. corneae in the murine model. If the simian model can be improved, the effective compounds will then be tested in monkeys, as well. FUNDING NIH; UO1AI0402 (J.A. Shadduck, P.I.); 05/01/96-04/31/00;$277,178 (year 3 total direct; subcontract = approx. 50% of total directs went to RPRC) NIH; NO1-AI-75327 (E.S. Didier, P.I.); 08/15/97-08/14/02; $360,781 (year 2 directs; 100% to RPRC) Venture research funding at TRPRC PUBLICATIONS Abstracts Snowden, K, E.S. Didier, and D. Phalen. 1998. What is the source of Encephalitozoon infections in immunocompromised humans? 49th Ann. Southwest Conference on Disease in Nature Transmissible to Man. College Station, TX (abstract). Snowden, K.F., J.A. Shadduck, and E.S. Didier. 1998. Evaluation of antimicrosporidial therapies using an immunedeficient mouse model. National Cooperative Drug Discovery Groups for the Treatment of Opportunistic Infections (abstract). Snowden, K., D. Phalen, and E.S. Didier. 1998 Where are the reservoirs of human microsporidial infections? Second European Congr. Trop. Med., Liverpool, U.K. (abstract 438) and Amer. J. Trop. Med. Hyg. 59:302 (abstract 554). Green, L.C., L.B. Rogers, P.J. Didier, and E.S. Didier. 1998. Enterocytozoon bieneusi infection immunocompromised rhesus monkeys. Amer. J. Trop. Med. Hyg. 59:332 (abstract 644). Reviews and book chapters Didier, P.J., E.S. Didier, K. Snowden, and J.A. Shadduck. 1998. Encephalitozoonosis. In Infectious Diseases of the Dog and Cat. C.E. Greene (ed.). W.B. Saunders, Philadelphia, PA. pp. 465-469. Didier, E.S., K.A. Snowden, J.A. Shadduck. 1998. The biology of Microsporidian species infecting mammals. Adv. Parasitol. 40:279-316. Didier, E.S. 1998. State-of-the-Art Clinical Article Microsporidiosis. Clin. Infect. Dis. 27:1-7. Didier, P.J., E.S. Didier, and K.F. Snowden. 1998. Microsporidiosis Not just a disease of rabbits. Newsletter Amer. Comm. Lab. Anim. Dis. 19:3-7. Soave, R. and E.S. Didier. 1999. Cryptosporidium and Microsporidium. In Textbook of AIDS Medicine (2nd ed.). T.C. Merigan, J.G. Bartlett, and D. Bolognesi (eds.). Williams and Wilkins, Baltimore, MD. pp. 327-356. Didier, E.S. and G.T. Bessinger. 1999. Host-parasite relationships in microsporidiosis animal models and immunology. In:The Microsporidia and Microsporidiosis. M. Wittner (ed.). American Society for Microbiology, Washington, D.C. pp. 225-257. Didier, E.S. 1999. Immunology of Microsporidiosis. In Contributions to Microbiology. F. Petry (ed). S. Karger AG, Basel, Switzerland (in press). K.F. Snowden, E.S. Didier, J.M. Orenstein, and J.A. Shadduck. 1999. Animal models of human microsporidial infections. In Animal Models. Armed Forces Institute of Pathology, Washington, D.C. (in press).

微孢子虫引起艾滋病患者的机会性感染，器官移植接受者、儿童和旅行者。肠细胞虫 bieneusi 是最流行的小孢子虫，但试图建立了产生生物体的组织培养系统不成功。已知的 E. bieneusi 唯一的非人类宿主包括猪和非人类灵长类动物（例如猕猴）。 10 名 SIV 感染者恒河猴口服接种了从以下来源收获的 E. bieneusi 人类艾滋病患者的粪便和十二指肠灌洗液抽吸物。一周后在粪便中检测到孢子并继续偶尔持续约两年或直至死亡猴子，但孢子脱落的不一致目前使得该模型不足以测试抗微孢子虫化合物。然而，猴子确实感染了 E. bieneusi，并且在胆囊中发现了与寄生虫相关的病变，肝脏、小肠。试图感染小动物（例如。沙鼠、hymic 小鼠、免疫抑制小鼠）以及 E. bieneusi 也至今未能成功。由于建立一个有用的 E. bieneusi（一种替代微孢子虫，Vittaforma）的动物模型目前正在使用角膜来开发用于测试的动物模型体内的先导化合物。无胸腺小鼠出现消瘦（恶病质）和腹腔内接种5种后15-60天出现腹水并死亡 x 107 - 1 x 104 V. 角膜生物。无胸腺小鼠感染 1 x 107 例用烟曲霉素治疗的角膜仅存活了几天比未治疗的小鼠长，但有统计学意义小动物中与寄生虫相关的病变明显减少接受治疗的小鼠的肠、胆囊和肝脏。自从烟曲霉素对哺乳动物有毒，正在尝试获得夫马洁林用于测试抗角膜弧菌的类似物和相关化合物小鼠模型。如果能够改进猿猴模型，则有效随后还将在猴子身上测试化合物。资助国立卫生研究院； UO1AI0402（J.A.沙达克，P.I.）； 05/01/96-04/31/00；277,178 美元（第 3 年总直接；分包合同=约。总直接流量的 50% 流向 RPRC）美国国立卫生研究院； NO1-AI-75327（E.S. Didier，P.I.）； 97年8月15日-2002年8月14日； 360,781 美元（第 2 年指导；100% 给 RPRC）风险研究资金 TRPRC 出版物摘要 Snowden, K, E.S.迪迪埃和 D.法伦。 1998. 脑炎原虫感染的来源是什么免疫功能低下的人类？ 49 安.西南疾病会议在自然界中可传染给人类。德克萨斯州大学城（摘要）。斯诺登，K.F.，J.A.沙达克和E.S.迪迪埃. 1998. 评价使用免疫缺陷小鼠模型进行抗微孢子虫治疗。国家合作药物发现小组治疗机会性感染（摘要）。斯诺登，K.，D. Phalen，和 E.S. 迪迪埃. 1998 人体微孢子虫的储存库在哪里感染？第二届欧洲议会特罗普。医学博士，利物浦，英国（摘要 438）和阿米尔。 J.特罗普. 医学。卫生。 59:302（摘要 554）。格林，L.C.，L.B.罗杰斯、P.J.迪迪埃和 E.S.迪迪埃. 1998. 比氏肠细胞虫感染免疫功能低下的恒河猴。阿米尔。 J.特罗普. 医学。卫生。 59:332（摘要 644）。评论和预订章节 Didier, P.J., E.S.迪迪埃 (Didier)、K. 斯诺登 (K. Snowden) 和 J.A.沙鸭。 1998.脑炎动物病。狗的传染病和猫。 C.E.格林（编）。 W.B.桑德斯，宾夕法尼亚州费城。页数 465-469。迪迪埃，E.S.，K.A.斯诺登，J.A.沙鸭。 1998 年。感染哺乳动物的微孢子虫物种的生物学。副词。寄生虫醇。 40：279-316。迪迪埃，E.S. 1998. 最先进的临床文章微孢子虫病。临床。感染。迪斯。 27:1-7。迪迪埃，P.J.，E.S. 迪迪埃和 K.F.斯诺登。 1998. 微孢子虫病不仅仅是一种疾病兔子。时事通讯阿米尔。通讯。实验室。动画。迪斯。 19:3-7。索阿韦, R.和E.S.迪迪埃. 1999.隐孢子虫和微孢子虫。在艾滋病医学教科书（第二版）。 T.C.梅里根，J.G.巴特利特和 D.博洛涅西（编辑）。威廉姆斯和威尔金斯，马里兰州巴尔的摩。页数 327-356。迪迪埃，E.S.和G.T.贝辛格。 1999. 宿主-寄生虫微孢子虫病动物模型和免疫学的关系。在：微孢子虫和微孢子虫病。 M.维特纳（主编）。美国人微生物学会，华盛顿特区，第 225-257 页。迪迪埃，E.S. 1999.微孢子虫病的免疫学。在贡献中微生物学。 F.佩特里（编辑）。 S. Karger AG，瑞士巴塞尔（位于按）。 K.F.斯诺登，E.S.迪迪埃 (Didier)、J.M. 奥伦斯坦 (J.M. Orenstein) 和 J.A.沙鸭。 1999.人类微孢子虫感染的动物模型。在动物中模型。武装部队病理学研究所，华盛顿特区（于按）。