Characterization of the C. elegans transcription factor ZIP-1 and other regulators of the intracellular pathogen response

• Applicant: Dr. Nicole Wernet
• Subject Area: Immunology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510766555

Within the last decades, the nematode Caenorhabditis elegans has become an important model organism for the study of host-pathogen interactions. Numerous C. elegans pathogens have been described and the study of these interactions have allowed the characterization and identification of many components and signaling cascades of the innate immune system. Microsporidia are among the most commonly described C. elegans pathogens in nature. These obligate intracellular pathogens of nematodes are relatives of fungi. They can infect a variety of hosts, including humans. An examination of the host response of C. elegans to infection with Nematocida parisii revealed that the immune response is almost identical to that against the Orsay virus, a molecularly vastly different organism. This shared transcriptional immune response has been termed the intracellular pathogen response (IPR) and results in increased resistance to infection, as well as increased proteostasis. Many aspects of the IPR and the precise mechanisms of its regulation remain to be investigated. Prof. E. Troemel's laboratory recently identified the leucine zipper (bZIP) transcription factor ZIP-1 as a master regulator of the IPR, that is required for the induction of numerous IPR genes downstream of all IPR triggers tested. However, overall, ZIP-1 is only responsible for the induction of less than half of the IPR genes, indicating the presence of at least one other regulator. This project aims to identify additional transcription factors involved in the induction of ZIP-1-independent genes. Furthermore, it is still unclear how ZIP-1 itself is activated. Only in the case of the Orsay virus infection it is described that the RIG-I-like receptor DRH-1, which detects viral replication products, seems to play a role in the activation of ZIP-1. To investigate how ZIP-1 is activated downstream of the other IPR triggers, genome-wide and genetic screening methods will identify regulators upstream of ZIP-1. Further open questions on the mechanisms of gene regulation by ZIP-1 will be addressed within the scope of the proposed project. To this end, transcription factor binding sites in the genome will be identified. This will help to clarify whether ZIP-1 activates the IPR genes directly or indirectly. In addition, the general role of chromatin remodeling in the regulation of IPR will be analyzed. The goal of this project is to characterize the mechanism of regulation of the IPR by ZIP-1, as well as to identify additional regulators of this immune response. Thus, new aspects of the host response of C. elegans to intracellular pathogens will be elucidated and the underlying signaling cascades of epithelial immunity will be explored.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Emily Troemel