Therapeutic suppression of alveolar echinococcosis

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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).