Antivirally active factors of the type I interferon systems of small mammals

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The interferon (IFN) system represents an important species barrier and control instance against invading viruses. Cells can sense viral infection by means of pathogen recognition receptors (PRRs), and respond by synthesizing and secreting IFN-alpha/beta. The binding of IFNs to their cognate receptor on surrounding cells leads to the expression of more than 350 IFN-stimulated genes (ISGs). Several ISG products possess antiviral properties, thus controlling viral replication and spread. The IFN system of bats and other small mammals is ill characterized so far, although it is suspected to be mainly responsible for the ability of these animals to serve as reservoirs for zoonotic viruses. To fill this knowledge gap, we established during the first funding period molecular tools and started generating genome-wide, virus- and IFN-responsive transcriptomes of Myotis daubentonii. From that species we also cloned, expressed, and characterized the main PRRs and ISGs, namely RIG-I and Mx1, respectively, as well as Mx1 proteins from six additional bat and five rodent species. Our preliminary results show that these key IFN factors are functional, but can differ from their human counterparts.Having now established a firm experimental basis, we want to build on our achievements in the second funding period. Our goals are to (i) complete the virus- and IFN-induced transcriptomes of bats, (ii) compare with the corresponding human transcriptomes and evaluate and characterize interesting hits, (iii) perfom an in-depth comparison of RIG-I and Mx proteins of humans, bats, and rodents, and (iv) define the antiviral spectrum of these key IFN factors. Identification and characterization of similarities and differences in the IFN systems will help to understand why reservoir species are better coping with viruses than humans.