Deciphering the interferon system in bats

Background:Bats are the second most speciose group of mammals after rodents, with more than 1400 species that comprise over 20% of all known mammalian species. While several important aspects of bat physiology and behaviour have been studied intensively over the last decades, the importance of bats as a reservoir host for emerging and re-emerging viruses has become increasingly apparent after several recent viral outbreaks. Many of these viruses pose a serious risk to both human and animal health, as illustrated by recent outbreaks of Hendra virus, Nipah virus, Ebola and Marburg viruses, SARS coronavirus (SARS-CoV), and most recently by SARS-CoV-2, the causative agent of COVID-19. One key unresolved question in the field is why there are so few documented cases of virus-related disease in bats given the high prevalence of viruses hosted by these mammals, which raises the pertinent question; what makes bats an "ideal" reservoir host for so many emerging viruses.Working hypothesis and aims:Despite the importance of bats as a reservoir host for many emerging and re-emerging viruses, our current understanding of virus - host interactions in bats, and in particular our knowledge of the interferon (IFN) system in bats, remains rudimentary. While much progress has been made in recent years, most of the underlying viral and host determinants affecting the successful establishment and immune control of viral infections in bats remain elusive. Herein, a major hurdle is the lack of an appropriate unified biologically relevant model system and molecular tools to study virus - host interactions in bats that can be directly compared to analogous models of other mammals. As a first step toward deciphering the IFN system in bats we will (I) establish a primary cell culture repository of bat airway epithelial cells and (II) a bat-specific molecular tool box to determine (III) the biological role of type I and III IFNs in bats and (III) cellular distribution of key components of the bat IFN system. Finally, we will (IV) functionally characterize the bat IFN response during virus replication to gain a deeper insight of the bat innate immune response during viral infection.Expected Significance:The proposed studies will generate novel and detailed knowledge on the biological role of type I and III IFNs in bats and will specifically determine how the bat IFN response is temporally regulated within the heterologous respiratory epithelium in the context of viral infection and whether this is different from other mammals, such as humans. This knowledge is of high impact given the importance of bats as potential reservoir hosts for so many emerging viruses and will be indispensable to better understand what makes bats 'special' as reservoir hosts for so many emerging viruses.