Project description
Unravelling human innate immune recognition pathways
One of the hallmarks of antiviral defence is the sensing of foreign nucleic acids by pattern recognition receptors found on cells of the innate immune system. This recognition leads to responses by the sensing cell all the way to the induction of adaptive immune responses. Funded by the European Research Council, the GENESIS project proposes to investigate nucleic acid sensing pathways in human cells. Researchers will develop a high-throughput, genome-targeting platform for large-scale loss-of-function studies. They will explore the roles, cooperativity and redundancy of nucleic acid sensing pathways as well as the downstream signalling events. Findings are expected to provide unprecedented insights into innate immune signalling pathways in human cells.
Objective
In vertebrates, a receptor-based, innate sensing machinery is used to detect the presence of microbederived molecules or the perturbation microbial infection causes within the host. In the context of viral infection, non-self nucleic acids are sensed by a set of intracellular receptors that upon activation initiate broad antiviral effector responses to eliminate the imminent threat. Over the past years our understanding of these processes has considerably grown, mainly by employing murine knockout models.
Recent advances in genome engineering now provide the opportunity to knockout genes or even to perform functional genetic screens in human cells, providing a powerful means to validate and generate hypotheses. We have developed a high-throughput genome targeting and validation platform that allows us to tackle large-scale loss-of-function studies both at a polyclonal as well as an arrayed format. In addition, we have invested considerable efforts to render this technology applicable to study innate immune sensing and signalling pathways in the human system. GENESIS will combine these efforts to tackle pertinent questions in this field that could not have been addressed before: We will systematically dissect known nucleic acid sensing pathways in the human system to explore their unique roles, cooperativity or redundancy in detecting non-self nucleic acids. We will perform polyclonal, genome-wide loss-of-function screens to elucidate signalling
events downstream of intracellular DNA and RNA sensing pathways and their roles in orchestrating antiviral effector mechanisms. Moreover, in a large-scale perturbation study, we will specifically address the role of the kinome in antiviral innate immune signalling pathways, exploring the role of its individual members and their epistatic relationships in orchestrating gene expression. Altogether, these studies will allow us to obtain insight into innate immune signalling pathways at unprecedented precision, depth and breadth.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesbasic medicineimmunologyautoimmune diseases
- natural sciencescomputer and information sciencesartificial intelligencepattern recognition
- natural sciencesbiological sciencesgeneticsRNA
Keywords
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
80539 Muenchen
Germany