Abstract
The emergent zoonotic henipaviruses, Hendra, and Nipah are responsible for frequent and fatal disease outbreaks in domestic animals and humans. Specificity of henipavirus attachment glycoproteins (G) for highly species-conserved ephrin ligands underpins their broad host range and is associated with systemic and neurological disease pathologies. Here, we demonstrate that Cedar virus (CedV)-a related henipavirus that is ostensibly nonpathogenic-possesses an idiosyncratic entry receptor repertoire that includes the common henipaviral receptor, ephrin-B2, but, distinct from pathogenic henipaviruses, does not include ephrin-B3. Uniquely among known henipaviruses, CedV can use ephrin-B1 for cellular entry. Structural analyses of CedV-G reveal a key region of molecular specificity that directs ephrin-B1 utilization, while preserving a universal mode of ephrin-B2 recognition. The structural and functional insights presented uncover diversity within the known henipavirus receptor repertoire and suggest that only modest structural changes may be required to modulate receptor specificities within this group of lethal human pathogens.
Highlights
The prototypic henipaviruses (HNVs), Hendra virus (HeV), and Nipah (NiV) virus are biosafety level four (BSL4) pathogens responsible for severe human disease that is associated with rapid onset and case fatality rates that can exceed 90% [1, 2, 3]
Reported to use the common entry receptor, ephrin-B2 [19, 35], Cedar virus (CedV)-G is genetically distinct from all characterized ephrintropic HNVs (26%, 28%, and 31% identical to Ghanaian bat henipavirus G (GhV-G) [Ghana virus], Hendra virus G (HeV-G), and Nipah virus G (NiV-G), respectively) [27]
The identification of HeV and NiV was a consequence of their emergence as the etiological agents of severe respiratory and neurological disease, targeted virus discovery efforts have demonstrated utility in identifying novel HNVs yet to be linked with symptomatic illness [10, 11, 19]
Summary
The prototypic henipaviruses (HNVs), Hendra virus (HeV), and Nipah (NiV) virus are biosafety level four (BSL4) pathogens responsible for severe human disease that is associated with rapid onset and case fatality rates that can exceed 90% [1, 2, 3]. The extreme disease pathologies, absence of a licensed vaccine, paucity of medical intervention options, and zoonotic potential delineate HNVs as an acute and persistent threat to global biosecurity, economy, and health [4]. Zoonotic spillover is typically associated with transmission from chiropteran reservoirs, or via infection of domestic animal intermediates, such as pigs and horses, transmission is not restricted to cross-species spillover events. The indirect association of a novel HNV, Mójiang virus (MojV), with the death of three miners in China highlights the potential of non-chiropteran hosts as reservoirs of lethal HNVs [17]. The continued discovery and emergence of novel HNV species underscores the indeterminate global health threat that they pose [4, 12]
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