Abstract

SUMMARY Several examples of high-impact cross-species transmission of newly emerging or re-emerging bat-borne viruses, such as Sudan virus, Nipah virus, and severe acute respiratory syndrome coronavirus 2, have occurred in the past decades. Recent advancements in next-generation sequencing have strengthened ongoing efforts to catalog the global virome, in particular from the multitude of different bat species. However, functional characterization of these novel viruses and virus sequences is typically limited with regard to assessment of their cross-species potential. Our understanding of the intricate interplay between virus and host underlying successful cross-species transmission has focused on the basic mechanisms of entry and replication, as well as the importance of host innate immune responses. In this review, we discuss the various roles of the respective molecular mechanisms underlying cross-species transmission using different recent bat-borne viruses as examples. To delineate the crucial cellular and molecular steps underlying cross-species transmission, we propose a framework of overall characterization to improve our capacity to characterize viruses as benign, of interest, or of concern.