PathAutoBIO · Uncovering the pathway of DNA-induced autophagy and its biological functions in viral central nervous system infection
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-05-01 → 2020-04-30
- EU contribution
- €200,195
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Uncovering the pathway of DNA-induced autophagy and its biological functions in viral central nervous system infection
The host mobilizes a series of responses against invading pathogens. However, pathogens have developed a wide range of strategies to counteract or hijack these responses. Hence, a deep understanding of the different defense mechanisms against infection and their regulation by pathogens is critical for development of new therapeutic strategies. The innate immune system constitutes the first line of defense against infections and is rapidly activated after sensing of pathogen- and abnormal self-derived molecules. For instance, cytoplasmic DNA can be detected by a variety of immune sensors, notably the key sensor cGAS. In most cases, these sensors require the function of the adaptor protein STING to lead to the production of interferons and other molecules playing important roles in inflammation and defense against pathogens. It is well established that sensing of foreign DNA and STING functions play a central role in the defense against a wide range of bacterial and viral infections. On the other hand, excessive STING activation is linked to disproportionate inflammatory responses and could lead to inflammation-driven carcinogenesis or autoimmune disease. A fine-tuning of STING functions is thus absolutely required to ensure both protective immunity and limitation of uncontrolled inflammation. Interestingly, our lab and others showed that DNA sensing activates autophagy, an ancient and conserved catabolic process involved in metabolic recycling but also degradation of pathogens and positive and negative regulation of immune responses. Importantly, our knowledge of the cross-regulations between autophagy and innate immunity and their modulation by pathogens, including viruses, is fragmented. In particular, a comprehensive view of the connections between STING and autophagy is missing. Our project aim at deciphering the pathway of this newly discovered autophagy-activating function of the cGAS-STING axis. Especially, we aim at defining the involvement of known molecules of the autophagy pathway in this mechanism, identify STING-interacting proteins involved in STING-mediated autophagy and uncover their mode of action. This project allowed us to uncover that STING pathways leading to autophagy and to immune responses are at least partially distinct. We also found that STING-mediated autophagy represent a previously unsuspected non-canonical autophagy pathway.
Data: CORDIS, © European Union
Project objective
Pathogens establish a range of strategies to efficiently infect and persist in their hosts. These mechanisms are as varied as pathogens themselves, which poses many difficulties for fighting infections. A deep understanding of host defense mechanisms is thus crucial for developing innovative therapies. Sensing of pathogen-derived nucleic acids is pivotal for induction of host defense. The adaptor molecule STING plays a central role in this defense and coordinate activation of immune responses. Recent studies showed that cytosolic DNA sensing and subsequent STING activation also leads to induction of autophagy, a degradative pathway involved in metabolic recycling and regulation of infections and immunity. Both STING and autophagy are involved in a range of diseases e.g. infectious and autoimmune diseases, neurodegeneration and cancers. However, the links between STING and autophagy and their regulation of the balance between protective responses and harmful inflammation is elusive. Likewise, the roles of STING-mediated autophagy during viral infections is unknown. Using cutting-edge tools e.g. ImageStream X flow cytometry and genome-editing of human stem cells-derived brain cells using CRISPR/Cas9, PathAutoBIO will decipher the pathway of this novel STING function. We will then combine in vitro and in vivo models of central nervous system viral infection to explore STING-mediated autophagy functions at this unique site, where autophagy and STING are important for viral clearance. We will build upon the expertise of the host lab in DNA sensing, take advantage of unique tools developed for the project, and integrate leading international collaborators. Combined with my strong background in infection cell biology, our work will provide insights on the cross-regulations between autophagy and immunity. This will lead to a broader understanding of mechanisms regulating diseases presenting global threats for societies and will help the design of broad-spectrum therapies.
Original text from CORDIS.
Participants
- AARHUS UNIVERSITET · Aarhus CCoordinatorDenmark
Links
Data: CORDIS, © European Union