Role of the multi-functional translation initiation factor eIF3 complex in host-pathogen interaction

• Applicant: Dr. Dieter A. Wolf
• Subject Area: Cell Biology ; Parasitology and Biology of Tropical Infectious Disease Pathogens ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506550226

There are more than 20 Leishmania species that cause a multitude of clinical manifestations, ranging from self-healing cutaneous sores to the more severe mucocutaneous or lethal visceral forms. Although leishmaniases are endemic in parts of Asia, Africa, the Americas and Southern Europe, affecting the populations of over 88 countries, they are still considered neglected diseases. Available drugs are highly toxic requiring close medical follow-up and occasional hospitalization. Climate change and rapidly emerging drug resistance will lead to continued spread, creating a strong unmet medical need. Basic research toward understanding mechanisms of infection and host susceptibility is crucial for the discovery of novel drug targets for combating leishmaniases. Combining their expertise in mammalian cell biology (Wolf) and in parasitology (Shapira), the collaborating labs will launch a two-pronged approach to decipher mechanisms of post-transcriptional control of parasite virulence and host defense as well as their interplay. Leishmania is peculiar because its gene expression is not controlled at the level of transcription. Rather, its complex life cycle relies on sophisticated post-transcriptional mechanisms, especially those operating at the level of mRNA translation. Leishmania has dramatically expanded its repertoire of translation factors apparently to accomplish mRNA-selective translation required for growth and survival in different environments. Our recent work showed that Leishmania encodes a functional set of the 12 subunits of the eukaryotic translation initiation factor eIF3 some of which, such as LIF3a, enable non-canonical pathways of translation. In mammals, our work has advanced the concept that eIF3 has a modular architecture with different modules mediating distinct functions in mRNA-selective translation. For example, the eIF3d-eIF3e module is selectively promoting translation elongation of mRNAs encoding ~2,600 proteins with membrane-associated functions, including lysosomal proteins. The central importance of translational control in parasite physiology together with the requirement of eIF3 for host lysosomal function led to the hypothesis that eIF3 is both a crucial host as well as pathogen factor. Synergizing through their complementary expertise in parasite, RNA, and mammalian cell biology, the collaborating investigators will address this overarching hypothesis in three aims: (i.) Characterize the function of Leishmania eIF3 subunits in mRNA selective translation; (ii.) Characterize the function of eIF3 in mRNA selective translation in macrophages, (iii.) Characterize the mutual interplay of host and pathogen eIF3 in Leishmania infection/pathogenicity. Through these investigations, eIF3 may emerge as both a factor critical for pathogenicity as well as representing a new drug target in leishmaniasis. At the same time, these efforts will foster collaboration between leading labs in Israel and Germany.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professorin Dr. Michal Shapira