Trypanosome differentiation and host interaction (Boshart)
A successful parasitic life strategy of pathogens requires cellular adaptation to changing host environments and effective signaling to control the host-parasite interaction. Trypanosoma and Leishmania are protozoan parasites and important tropical pathogens transmitted by blood-sucking insect vectors. They cause severe and difficult-to-treat human diseases. How can these parasites withstand the sophisticated host defense? How do they sense their host environment and regulate their stage development to adapt? The Boshart group studies a signaling pathway that uses the small molecule cAMP to transmit information. We have shown that early in an infection, trypanosomes secrete the signaling molecule cAMP to silence the mammalian immune cells that otherwise kill them. Upon transmission by the tsetse fly, the change in body temperature induces differentiation by activating a protein kinase A that resembles the conserved target protein of cAMP in most organisms. Although we have learned that some conserved components of cAMP signaling are used for essential parasite signaling, they work together in a very different way and a novel cAMP signaling cascade completely specific for these organisms has been identified and controls cell division. Repurposing of signaling modules during the evolution becomes particularly evident in these distant protozoa. Besides the fundamental interest in mechanisms of signaling, this is an opportunity to identify potential drug targets sufficiently different from the mammalian host to achieve therapeutic specificity. Structure guided development of agonists and inhibitors of these signaling pathways shows promising results.