Therapeutic suppression of alveolar echinococcosis

肺泡棘球蚴病是由多房棘球蚴引起的一种严重且经常致命的人类寄生虫感染。虽然人类体内的寄生虫最初几乎只存在于肝脏中，但它会通过浸润或转移的形式扩散到其他器官。一旦出现症状，未经治疗或治疗不充分的肺泡包虫病的死亡率非常高，10年生存率不到30%。据估计，西欧和中欧每年新发肺泡包虫病病例在170 - 200例之间，奥地利和德国也受到影响。肺泡包虫病的治疗选择包括手术和苯并咪唑的持续治疗。此外，一些其他药物也在研究中。然而，尽管两性霉素B已被用作不能耐受苯并咪唑的患者的补救性治疗，但在人类中使用它们都没有表现出理想的效果。基于现有的文献数据，我们确定了一种特定的蛋白质，可能在多房棘球绦虫的侵袭性生长中起关键作用。我们的初步数据表明，在缺乏这种蛋白质的转基因小鼠中，与野生型对照相比，摄入多房棘球绦虫卵后，囊肿的平均重量大幅减少。在感染多房棘球绦虫的人类中，已经证明主要是细胞免疫反应（Th1淋巴细胞介导）导致对寄生虫的保护，而主要是体液免疫反应（Th2淋巴细胞介导）伴随着疾病进展。这表明向Th2反应的转变可能依赖于白细胞介素-4水平。在IL-4受体缺陷小鼠中分析这些参数对于确定多房棘球绦虫如何影响宿主免疫系统，以及剖析Th2细胞因子IL-4在肺泡包虫病中的作用具有重要意义。此外，使用表达人类先天免疫系统的小鼠将使我们能够在部分人源化模型系统中评估假设的囊肿生长和免疫系统的相互作用。最后，为了评估假定的治疗结果，我们将在感染多房棘球绦虫的野生型小鼠中应用临床用于长期抑制我们的候选蛋白的药理抑制剂。该项目将在PI Johann Wojta博士、国家研究伙伴Pavel Uhrin博士（维也纳医科大学）以及寄生虫学家Thomas Romig博士和Marion Wassermann博士（霍恩海姆大学）的合作努力下完成。

Alveolar echinococcosis is a serious and often fatal parasitic infection of humans instigated by Echinococcus multilocularis. Although the parasite in humans is initially almost exclusively present only in the liver, it spreads to other organs, by infiltration or metastasis formation. Once symptomatic, mortality rates in untreated or inadequately treated alveolar echinococcosis are very high with a 10 year survival of less than 30%. The estimated number of new alveolar echinococcosis cases in Western and Central Europe are in the range of 170 - 200 per year and also Austria and Germany are affected. Treatment options for alveolar echinococcosis include surgery and the continuous medical treatment with benzimidazoles. In addition, a number of other drugs have been under study. However, use of none of them exhibited desirable effects in humans, although amphothericin B has been used as a salvage treatment in patients who did not tolerate benzimidazoles.Based on the available literature data we identified a certain protein that might play a crucial role in invasive growth of the parasite E. multilocularis. Our preliminary data demonstrate a massive reduction in the average weight of the cysts following E. multilocularis eggs’ ingestion, in transgenic mice lacking this protein as compared to the wild-type controls. In humans infected with E. multilocularis, it has been shown that a predominantly cellular immune response (Th1 lymphocyte-mediated) results in protection against the parasite while a predominantly humoral immune response (Th2 lymphocyte mediated) is accompanied by disease progression. It was suggested that a shift towards a Th2 response may be dependent on interleukin-4 levels. Analyzing these parameters in IL-4 receptor-deficient mice will be important for determining how E. multilocularis affects the immune system of the host, and for dissecting the role of the Th2 cytokine IL-4 in alveolar echinococcosis. Furthermore, use of mice expressing a human innate immune system will allow us assessing the hypothesized interplay of cyst growth and immune system in a partially humanized model system. Finally, to evaluate the putative therapeutic outcome, we will apply to wild-type mice infected with E. multilocularis a pharmacological inhibitor clinically used in patients for long-term inhibition of our candidate protein. The project will be accomplished in a cooperative effort between the PI Dr. Johann Wojta, the national research partner Dr. Pavel Uhrin (Medical University of Vienna) and the parasitologists Dr. Thomas Romig and Dr. Marion Wassermann (University of Hohenheim).