INFECTIVITY OF CRYPTOSPORIDIUM PARVUMFOR ADULT HUMANS

隐孢子虫现在被认为是健康和免疫功能低下宿主腹泻的重要原因。它经常出现在成品饮用水中，即使遵循现行的水处理标准也很难根除。隐孢子虫病的治疗是次优的，在某些人群中（如艾滋病患者），它可能导致显著的发病率。隐孢子虫已被医学研究所确定为一种健康威胁，并且作为总统安全食品倡议的一部分，已成为环境保护局和食品和药物管理局从水和食品中根除的目标。隐孢子虫包括一个异质种群，传统上按宿主偏好分类，最近通过基因型分析进行分类。小隐孢子虫被认为是唯一可以感染人类的物种；然而，非幼种对人类的传染性尚未得到研究。细小弧菌种类分为感染人类的（基因型H）和在人和动物宿主之间传播的（基因型C）。在以前的研究中，健康成人的实验性隐孢子虫病已经揭示了对地理上不同的基因型C分离株的传染性、结局和免疫反应的变异性。然而，很大比例的自然获得性隐孢子虫病病例是由于H基因型。H基因型分离物在非生仔猪中的成功传代将使我们能够将自愿研究扩展到包括H基因型分离物。比较感染剂量、临床症状和免疫反应。这些分离株的相对毒力将在隐孢子虫病的实验室模型中相互关联。此外，我们将在实验感染隐孢子虫卵囊后的不同时间点，通过检查有和无症状的正常志愿者的肠道活检，确定与急性隐孢子虫病（损伤）、卵囊排泄（控制）和随后愈合相关的粘膜细胞因子。我们将通过开展IL-12作为艾滋病慢性隐孢子虫病辅助治疗的试点、概念验证、开放标签试验来确认Th1细胞因子在隐孢子虫病治疗中的作用。除了确定用于慢性艾滋病相关隐孢子虫病的制剂外，了解单个基因型感染的结果将有助于开发更准确的风险评估模型，用于预防地方性隐孢子虫病和由隐孢子虫引起的大规模水传播暴发。

Cryptosporidium is now recognized as an important cause of diarrhea in healthy and immunocompromised hosts. It is frequently found in finished drinking water and is difficult to eradicate even when current water treatment standards are followed. Therapy of Cryptosporidiosis is sub-optimal and in certain populations (such as people with AIDS) it can result in significant morbidity. Cryptosporidium has been identified as a health threat by the Institute of Medicine and has been targeted for eradication from water and food by the Environmental Protection Agency and the Food and Drug Administration as a part of the Presidential safe food initiative. Cryptosporidium encompasses a heterogeneous group of species that traditionally have been classified by host preferences and more recently by genotype analysis. Cryptosporidium parvum is thought to be the only species that can infect humans; however, the infectivity of non-parvum species for humans has not been studied. C.parvum species has been divided into those infecting humans (genotype H) and those that are transmitted between human and animal hosts (genotype C). In previous studies, experimental cryptosporidiosis in healthy adults has revealed variability in infectivity, outcome, and immune response to geographically-diverse genotype C isolates. However, a significant proportion of naturally acquired cases of cryptosporidiosis are due to the H genotype. The successful passage of genotype H isolates in gnotobiotic piglets will allow us to extend volunteer studies to include genotype H isolates. Comparisons of infectious dose, clinical syndromes and immune response will be done. The relative virulence of these isolates will then be correlated in laboratory models of cryptosporidiosis. In addition, we will identify the mucosal cytokines that are associated with acute cryptosporidiosis (INJURY), resolution of oocyst excretion (CONTROL), and subsequent HEALING by examining intestinal biopsies from normal volunteers with and without symptoms at different time points after experimental infection with Cryptosporidium oocysts. We will confirm the role of Th1 cytokines in resolution of cryptosporidiosis by conducting a pilot, proof-of-concept, open-label trial of IL-12 as adjunctive therapy in chronic cryptosporidiosis in AIDS. In addition to identifying an agent of use in chronic AIDS associated cryptosporidiosis, the understanding of the outcomes of infection with the individual genotypes will allow the development of more accurate risk assessment models useful in the prevention of endemic cryptosporidiosis and large scale waterborne outbreaks due to Cryptosporidium.