Canonical and non-canonical secretory mechanisms of cytokines in bat and human cell cultures in response to coronavirus infection: a comparative study

The majority of coronaviruses (CoV) originally emerged from bats including highly pathogenic SARS- and MERS-CoV. Bats evolved unique innate immune mechanisms that are likely responsible for the lack of immune pathology. One key process of the immune response is the secretion of cytokines, like interleukins (IL) and type I interferons (IFNs), however molecular details of cytokine secretions and their influence on the outcome of virus infections have not been studied in context of reservoir host species like bats. The aim of this research proposal is to determine the molecular mechanisms involved in the secretion of IL-1 and IFN in human and bat cells that could explain why bats have developed a tolerance against coronavirus infections. The training-through-research of the candidate will consist in analyzing the secretion of IFNs and IL-1 in cell culture supernatants of bat and human CoV-infected cells subjected to knockdowns of different molecules implicated in canonical or non-canonical secretory pathways, as well as activation and interactions between receptors of both secretory pathways. The multidisciplinary nature of the project is strong, involving a combination of well developed molecular biology, cell biology, and virology. This proposal includes both the transfer of knowledge to the host institution and the training of the candidate in new advanced techniques and transferable skills. The results will show in-depth mechanistic insights into bat cytokine secretion, which still has some gaps in its knowledge, and will serve as a promising platform for the development of new antiviral strategies to fight emerging zoonotic viruses, in line with the EU strategy listed Societal Changes of H2020 for the health, demographic change and wellbeing. The dissemination of the results to the scientific community will be done by publications in international open-access peer-reviewed journals, congresses, press releases and participation at science divulgation events.