Novel therapeutics, models and immune interations for cryptosporidiosis

为了与MARCE-2的目标保持一致，即开发广泛适用的新型治疗方法、模型和方法。 方法来改善先天和后天宿主防御重要的健康威胁，该项目建立 在开发新模型和量化临床和非临床研究的实质性进展和几篇出版物之后， 结果和强度和持续时间的感染与高度耐氯水传播 隐孢子虫属类特别是，我们的新生小鼠模型模拟了隐孢子虫感染的影响， 在人类中，在存在 营养不良我们现在有非常有希望的试点数据表明，关键的粘膜修复剂，包括 丙氨酰谷氨酰胺和精氨酸以及选定的候选疫苗（来自VCU和UMD合作）， 鼻内给药引起免疫应答， 隐孢子虫感染因此，我们广泛的长期目标是确定最佳的粘膜修复剂 以及它们与先天性和获得性免疫的驱动因素之间潜在的协同作用， 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）确定丙氨酰谷氨酰胺、精氨酸和APOE模拟肽的有效性， 在隐孢子虫感染之前或之后，2）确定这些之间的相互作用和潜在的协同作用， 粘膜修复剂与先天免疫的CpG、IMO或ClyA-pSEC疫苗载体驱动剂一起给予，或与 ClyA-CVD 908 htr-CP 15驱动适应性免疫应答;以及最后3）比较相对功效 以及上述定义的最佳方案与边际有效但最佳可用的 在我们的类器官和新生小鼠模型中， 隐孢子虫寄生虫。这种方法不仅将确定最佳的粘膜和免疫增强 隐孢子虫感染的方法，但与其他肠道感染有潜在的相关性， 疫苗也是。

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.