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Research Area B

Investigate the role of common & kingdom-specific infochemicals in mediating interactions between host immunity & host-microbe metabolic interdependencies.


Project 3: Survey and identify host-derived molecules that have regulatory roles on microbiomes (Prof. Dr. Filipe Cabreiro).

The function of members of the microbiota is highly modulated by environmental cues. Such dynamic interactions between xenobiotics and commensal bacteria are widely conserved in nature and observed from plants to lower invertebrates, and further in humans. Often, the impact of xenobiotics on microbes modulates microbial community dynamics and directly or indirectly, host function. Likewise, host-derived molecules (e.g metabolites, proteins) can also influence microbial dynamics either by acting as preferential substrates for some members of the community or by having inhibitory action through targeting essential processes in a wide range of phylogenetically
distant microbes. The central premise of this IP is to survey and identify host-derived molecules that have regulatory roles on microbiomes from diverse host organisms and unravel their mode of action. In particular, special attention will be paid to the role of the immune systems and in identifying common or unique host-microbe dependencies and unravelling their modes of action. i-HEAD is unique in its ability to bring together in an integrated manner host-microbe and metabolomics experts working on diverse trans-kingdom reductionist systems to address some of the most exciting questions in the field: How does a host modulate its microbiota? How does the host interpret such changes in microbial communities and adapt its metabolism and physiology? We strive to:

  • conduct high-throughput screening of animal- (C. elegans) and plant- (A. thaliana and C. reinhardtii) associated bacterial culture collections and host-derived metabolites and infochemicals
  • deciphering the interactions between host immunity signals and microbial metabolism
  • employing reductionist systems to unravel the role of immunity-related infochemicals in mediating host-microbe-immune-metabolic interdependencies
  • model host-microbe metabolic interdependencies and responses to immunity-related compounds

Project 4:  A barley MLA receptor is targeted by a nonribosomal peptide effector of the necrotrophic spot blotch fungus for disease susceptibility (Prof. Dr. Paul Schulze-Lefert).

In plants, the Toll/interleukin-1 receptor (TIR) domains of the nucleotide-binding leucine rich repeat (NLR) immunoreceptors possess NADase enzymatic activity, but this is not sufficient to activate plant immune responses (Duxbury et al., PNAS 2020). We have recently shown that plant TIR proteins also act as 2′,3′-cAMP/cGMP synthetases by hydrolyzing RNA/DNA (Yu et al., Cell 2022). Recent data support a role for 2′,3′-cAMP/cGMP in abiotic stress tolerance in A. thaliana (Van Damme et al., Phytochemistry 2014; Kosmacz et al., Plant Physiol 2018). In addition, 2′,3′-cAMP mediates stress granule formation (Kosmacz et al., Plant Physiol 2018), which mimics the abiotic stress response in A. thaliana (Chodasiewicz et al., Plant Physiol 2022). We will determine the dynamic changes in 2′,3′-cAMP/cGMP and other nucleotide metabolite pools in plant roots and root exudates in the absence and presence of bacterial SynComs under defined abiotic stress conditions (salt and drought stress). This will allow us to directly test the contribution of bacterial commensals to plant abiotic stress tolerance by modulating TIR-dependent immunometabolism (Berens et al., PNAS 2019). Hence, we aim to determine the dynamic changes in 2′,3′-cAMP/cGMP and other nucleotide metabolite pools in A. thaliana roots and root exudates in the absence and presence of bacterial SynComs under defined abiotic stress conditions (salt and drought stress).

Project 5: Interference of fungal root microbiota with TIR-mediated plant immunometabolism (Prof. Dr. Alga Zuccharo).

We recently showed that a TIR-NLR protein is involved in accommodation of beneficial fungi in the roots of A. thaliana by mediating a response to deoxyadenosine (dAdo), an active metabolite produced by the synergistic activity of fungal enzymes during root colonization (Dunken et al., bioRxiv 2023). The contribution of a TNL in dAdo-mediated fungal accommodation in Arabidopsis suggests that this NLR might be guarding a protein targeted by dAdo. Alternatively, as mentioned in IP 4, it is possible that dAdo is converted to a plausible substrate of TNLs related to either nicotinamide adenine dinucleotide (NAD) or to the non-canonical cyclic nucleotide monophosphate 2′,3′-cAMP (Horsefield et al., Science 2019; Wan et al., Science 2019; Yu et al., Cell 2022). We were able to show that this response is independent of EDS1, which raises the question of a new, EDS1-independent branch of immune metabolism in roots. Recently, it was shown that plant TIR proteins are not only NADases but also act as 2′,3′-cAMP/cGMP synthetases by hydrolysing RNA/DNA. Mutations that specifically disrupt synthetase activity abolish TIR-mediated cell death in N. benthamiana, demonstrating an important role for these cNMPs in TIR signaling (Yu et al., Cell 2022). The accumulation of extracellular 3′,5′-cAMP upon colonization with S. indica and treatment with dAdo links to cyclic nucleotide monophosphates (Dunken et al., bioRxiv 2023). In this IP we want to characterize the metabolism of dAdo in plant cells and how intracellular dAdo leads to TNL activation in Arabidopsis. Since NLRs of the TIR domain proteins are also found in animals, our results open the possibility to further investigate the role of TIR domain proteins in cell death triggered by dAdo in plants and beyond. In animal systems, it has been shown that dAdo-mediated toxicity following import of dAdo into macrophages involves conversion of dAdo to dAMP through the activity of deoxycytidine kinase (DCK) and adenosine kinase (ADK) and signaling via subsequent conversion to the corresponding di- and tri- phosphates by nucleotide kinases and activation of caspase-3-induced apoptosis (Winstel et al., mBio 2018). An open question here is: The absence of caspases in plants and the implication of an TNL in dAdo-mediated cell death in Arabidopsis strongly suggest that this part of the signaling pathway is not conserved between plants and animals and relies on different regulatory and execution mechanisms that need further investigation.

  • Characterization of novel nucleotide-based molecules involved in TIR-NLR-mediated immunity in A. thaliana roots during accommodation of beneficial and pathogenic fungi.
  • Identification of new active metabolites affecting fungal accommodation.