Novel therapeutics, models and immune interations for cryptosporidiosis

为了与Marce-2开发广泛适用的新疗法、模型和 改善针对重要健康威胁的固有和后天宿主防御的方法，该项目建立 基于实质性的进展和几个关于开发新模型和量化临床 高抗氯性水感染的结局、强度和持续时间 隐孢子虫。特别是，我们的新生小鼠模型模拟了隐孢子虫感染的影响 在人类中引起生长不足和极大地增加感染严重性的存在 营养不良。我们现在有非常有希望的试验数据表明，关键的粘膜修复试剂，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)， 给予鼻腔内诱导的免疫反应，以减少强度和生长损害 隐孢子虫感染。因此，我们广泛的、长期的目标是确定最佳的粘膜修复剂 以及它们与已知的先天免疫和获得性免疫的潜在协同作用 预防或改善隐孢子虫感染及其临床后果。我们的具体目标将是 因此：1)为了确定丙氨酰谷氨酰胺、精氨酸和APOE模拟肽的有效性，给出了 在隐孢子虫感染之前或之后，2)确定这些因素的相互作用和潜在的协同作用 粘膜修复剂与CpG、IMO或ClyA-PSEC疫苗载体驱动天然免疫或与 ClyA-CVD908htr-CP15驱动获得性免疫反应；最后3)比较 以及上面定义的最优方案与略微有效但最佳可用方案的潜在协同效应 抗原虫药物硝唑尼特在我们的器官类和新生小鼠模型中的作用 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 治疗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。

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.