X-KINGDOM-MIF - Cross-kingdom analysis of macrophage migration inhibitory factor (MIF) functions

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The chemokine-like mediator macrophage migration inhibitory factor (MIF) is a prominent human disease marker and a pivotal mediator of inflammatory, infectious and immune diseases including septic shock, colitis, malaria, rheumatoid arthritis, and atherosclerosis, as well as tumorigenesis. Translational applications emerging from MIF research have been delayed because of an incomplete mechanistic understanding of MIF´s pathobiology. Strikingly, MIF is an evolutionarily conserved protein that is found across kingdoms. Despite of its limited molecular size and lack of appreciable modular domains, MIF has been found to exhibit several sequential and three-dimensional structural motifs including two catalytic sites that provide this protein with a surprising functional complexity. In recent years, the applicants have significantly contributed to the elucidation of MIF structure and its role in human and plant disease and have performed comprehensive in silico characterization of plant MIFs. In the context of these findings, it is the aim of this joint ANR-DFG proposal to study the molecular links between MIF of human, plant and parasite (aphid) origin to identify potentially conserved functions in the regulation of immune responses between kingdoms. The applicants combine expert knowledge in immune regulatory mechanisms of human MIF and insect pathobiology as well as long-standing expertise in comparative plant immunity and molecular genetics of Arabidopsis thaliana and barley to study MIF functional and structural features in this cross-species/kingdom approach. They thus represent a unique interdisciplinary team combining in-depth expertise on MIF biochemistry, biology, and pathobiology, with plant genetics and biotechnology and infectious disease research. The collaborative project will enable us to shed first light on the role of plant and insect MIFs and on the functional relevance of the shared versus distinct motifs between the different kingdoms. We will systematically utilize the cross-kingdom analysis of MIF´s structure-function profile to better understand the mechanisms of MIF in infectious disease and plant immunity. In addition, the proposal will spark novel research into immune evasion mechanisms and evolutionary history of the MIF family.