Akito Koike     email
Institute for Hygiene and Microbiology

Supervisor:
Prof. Dr. Klaus Brehm (Würzburg)

Promotion Committee:
Prof. Dr. Klaus Brehm (Würzburg)
Prof. Dr. Christian Stigloher (Würzburg)
Dr. August Stich (Würzburg)   

Molecular analysis of the tapeworms' intra/intercellular signal transduction

Echinococcosis is one of the most important zoonoses. This parasitic disease posts a serious threat for human health. In addition to that, the substantial economic burden from the livestock production loss is also not negligible. Its morbidity ratio of human and livestock can be extremely high in the endemic area of some developing countries.     

One of the causative agents of echinococcosis is Echinococcus multilocularis. Its definitive hosts of this flatworm are carnivorous mammalians such as foxes and dogs. Its intermediate hosts are rodents. Rodents are infected when they ingest eggs in contaminated water or foods and the larvae migrate to the liver after hatching. They metamorphose into next larval stage called metacestodes, and repeat asexual reproduction. Eventually a lot of heads of adult worms called protoscoleces are formed inside of metacestodes. Through the food chain, the protoscoleces in the intermediate hosts are ingested by carnivores and lay eggs in their intestine after the development of reproductive organs. The feces of the definitive hosts including eggs again contaminate surrounding environment. Although humans are not natural intermediate host, when eggs are accidentally ingested, metacestodes show slow but massive growth mainly in liver. After long asymptomatic incubation period, this expansion can cause chronic liver failure. Because of the unlimited growth of larvae, echinococcosis in human patients can be fatal if it is left untreated. On the other hand, adult worms seldom do harm to canine patients.

Praziquantel is the most common drug for flatworm diseases, and it can exterminate adult worms in canine patients. However, it is not effective to metacestodes in human patients. The only choice of the contemporary chemotherapy for human echinococcosis is Albendazole, but this drug has two unignorable faults. First, it has adverse side effect because its target, β-tubulin is well conserved between human and flatworms. Second, it only stops the growth of metacestodes and cannot exterminate them. Without continuous medication, metacestodes regenerate themselves and patients can experience relapses. Therefore, there is strong demand for the development of new drugs which overcome these faults of Albendazole.

Brehm laboratory have developed in vitro culture system of metacestodes and stem cells isolated from them. Screening tests of various compounds are being performed with this system to find good targets of effective parasiticides. My main targets are protein kinases. Protein kinases regulate basically every function of a cell, but I am especially interested in the kinases which play key roles in inter/intracellular signal transduction and in the regulation of differentiation. In the view of evolutionary distance, some echinococcal kinases can be sufficiently different from human orthologues to develop selective but effective parasiticides.