Host immune effects on Echinococcus multilocularis developmental transitions

Abstract text

Introduction: The lethal zoonosis alveolar echinococcosis is caused by tumor-like growth of the metacestode larva of the tapeworm Echinococcus multilocularis within host organs. We previously established that the formation of the unusual metacestode is accompanied by drastic modifications of the parasite"s body axes. First, the anterior pole of the invading oncosphere is shut down within the host, resulting in the posteriorized, invasively growing metacestode. Later during an infection, the anterior pole is re-established which subsequently leads to the formation of numerous protoscoleces. How these modifications are regulated is unclear. Objectives: To investigate host influences on parasite developmental transitions and to characterize associated parasite signaling pathways. Materials & methods: We used parasite in vitro cultivation systems to study the influence of host cytokines on parasite development and differentiation, coupled with in situ hybridization and functional assays on parasite receptor systems. Results: We show that the formation of metacestode vesicles from parasite stem cells is significantly stimulated by physiological conditions of TNF-alpha, which is produced early during Echinococcus infections, by direct activation of a metacestode-specifically expressed TNF-alpha receptor through the host cytokine. We also show that TGF-beta, which accumulates around the metacestode during late stages of the infection, can directly stimulate Echinococcus TGF-receptors and induces the formation of brood capsules and protoscoleces in mature metacestode vesicles. Small molecule inhibitors against the parasite"s TGF-beta-receptors, on the other hand, blocked the formation of brood capsules and protoscoleces in otherwise unaffected, mature metacestode vesicles. Conclusions: Our data indicate that the Echinococcus-specific modulation of body axes which results in the formation of the metacestode is directly influenced by host cytokines that are formed during different phases of the immune response against the parasite. As such, the potentially parasitocidal, Th1-dominated immune response early during an infection fosters invasive parasite growth, whereas increased immune suppression around the parasitic lesions during late infections physiologically prepares E. multilcularis for the transmission to the next (definitive) host.