Novel therapeutics, models and immune interations for cryptosporidiosis

隐孢子虫病的新疗法、模型和免疫相互作用

基本信息

批准号：
7669846
负责人：
RICHARD L GUERRANT
金额：
$ 33.36万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-03 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7669846
关键词：
Adjuvant Agonist Animal Model Antigens Antiparasitic Agents Apolipoprotein E Arginine Automobile Driving Child Chlorine Clinical Collaborations Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Data Developed Countries Development Diarrhea Disease Disease Outbreaks Effectiveness Enteral Epithelial Goals Growth Health Host Defense Human Immune Immune response Immunity Immunocompromised Host Immunologic Adjuvants Impaired cognition Impairment Infection Malnutrition Modeling Mucous Membrane Mus Natural Immunity Neonatal Oligonucleotides Oocysts Organoids Outcome Parasites Peptides Persons Pharmaceutical Preparations Phase I Clinical Trials Preventive Protozoa Public Health Publications Publishing Relative (related person)Resistance Salmonella typhi Severities Stimulus Surface Testing Therapeutic Treatment Protocols Vaccines Water Work acquired immunity alanylglutamine base biodefense experience improved mimetics mouse model nitazoxanide novel novel therapeutics prevent public health relevance repaired vaccine candidate vector vaccine waterborne

项目摘要

In keeping with MARCE-2 goals of developing broadly applicable novel therapeutics, models, and approaches to improving innate and acquired host defenses for important health threats, this project builds upon substantial progress and several publications on developing new models and quantifying both clinical outcomes and intensity and duration of infection with the highly chlorine resistant water borne Cryptosporidium spp. In particular, our neonatal mouse model mimics the effects of cryptosporidial infections in humans causing both growth shortfalls and greatly increased infection severity in the presence of malnutrition. We now have very promising pilot data suggesting that key mucosal repair agents, including alanylglutamine and arginine as well as selected candidate vaccines (from VCU and UMD collaborations), given intranasally elicit immune responses that reduce both intensity and growth impairment from cryptosporidial infections. Thus, our broad, long term objective is to define the optimal mucosal repair agents and their potentially synergistic interactions with documented drivers of innate and acquired immunity to either prevent or ameliorate cryptosporidial infections and their clinical consequences. Our specific aims will therefore be: 1) to define the effectiveness of alanylglutamine, arginine, and APOE mimetic peptide, given before or after cryptosporidial infection, 2) to determine the interactions and potential synergies of these mucosal repair agents given with CpG, IMO or ClyA-pSEC vaccine vector drivers of innate immunity or with ClyA-CVD908htr-CP15 driving adaptive immune responses; and finally 3) to compare the relative efficacies and potential synergies of the optimal regimen defined above with the marginally effective, but best available anti-protozoal drug nitazoxanide in both our organoid and neonatal mouse models challenged with Cryptosporidium parasites. This approach not only will identify optimal mucosal and immune enhancing approaches to cryptosporidial infection, but will have potential relevance to other enteric infections and vaccines as well.

与MARCE-2的目标保持一致，该目标是开发广泛适用的新型治疗剂，模型和改善先天和获得的主机防御的方法，以实现重要的健康威胁，该项目建立经过重大进展和有关开发新模型并量化这两个临床的出版物高度耐氯的水的结果，强度和感染的持续时间隐孢子虫属。特别是，我们的新生小鼠模型模仿了隐孢子虫感染的影响在人类中，在存在下导致生长不足和在存在下的感染严重程度大大增加营养不良。我们现在有非常有前途的飞行员数据，表明关键的粘膜维修剂，包括丙酰谷氨酰胺和精氨酸以及选定的候选疫苗（来自VCU和UMD协作），考虑到鼻内引起免疫反应，从而减少了强度和生长障碍隐孢子虫感染。因此，我们广泛的长期目标是定义最佳粘膜修复剂以及他们与有记录的先天驱动因素和获得的免疫力的潜在协同互动预防或改善隐孢子虫感染及其临床后果。我们的具体目标将因此：1）定义给定给定的丙酰谷氨酰胺，精氨酸和APOE模拟肽的有效性隐孢子虫感染之前或之后，2）确定这些相互作用和潜在的协同作用用CPG，IMO或CLYA-PSEC疫苗媒介驱动器或具有先天免疫的粘膜维修剂或 Clya-CVD908HTR-CP15驱动适应性免疫反应；最后3）比较相对效率以及上面定义的最佳方案的潜在协同效应，但有效但最佳可用在我们的类器官和新生小鼠模型中，抗胃类药物硝酸药物均受到挑战隐孢子虫寄生虫。这种方法不仅可以识别最佳粘膜和免疫增强隐孢子虫感染的方法，但可能与其他肠道感染和疫苗也是如此。