Structure-guided identification of a nonhuman morbillivirus with zoonotic potential

Authors: ABDULLAH, NURSHARIZA - The Pirbright Institute; KELLY, JAMES - The Pirbright Institute; GRAHAM, STEPHEN - University Of Cambridge; BIRCH, JAMIE - The Pirbright Institute; GONCALVES-CARNEIRO, DANIEL - The Pirbright Institute; MITCHELL, TIM - University Of Birmingham; THOMPSON, ROBIN - University Of Oxford; LYTHGOE, KATRINA - University Of Oxford; LOGAN, NICOLA - University Of Glasgow; HOSIE, MARGARET - University Of Glasgow; BAVRO, VASSILIY - University Of Essex; WILLETT, BRIAN - University Of Glasgow; Heaton, Michael - Mike; BAILEY, DALAN - The Pirbright Institute

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/10/2018
Publication Date: 11/12/2018
Citation: Abdullah, N., Kelly, J.T., Graham, S.C., Birch, J., Goncalves-Carneiro, D., Mitchell, T., Thompson, R.N., Lythgoe, K.A., Logan, N., Hosie, M.J., Bavro, V.N., Willett, B.J., Heaton, M.P., Bailey, D. 2018. Structure-guided identification of a nonhuman morbillivirus with zoonotic potential. Journal of Virology. 92(23):e01248-18. https://doi.org/10.1128/jvi.01248-18.
DOI: https://doi.org/10.1128/jvi.01248-18

Interpretive Summary: A significant proportion of viral pandemics occur following zoonotic transmission events, where animal-associated viruses jump species into human populations. In order to forewarn against the emergence of these viruses it is necessary to develop a better understanding of what determines virus host-range, often at the genetic and structural level. In this research paper, we demonstrate that the small ruminant morbillivirus, a close relative of measles, is unable to use human receptors to enter cells; however, a change of a single amino acid in the virus is sufficient to overcome this restriction. This information will be important for monitoring this virus’s evolution in the field. Of note, this study was undertaken in vitro, without generation of a fully infectious virus with this phenotype.

Technical Abstract: Morbilliviruses infect a broad range of mammalian hosts, including ruminants, carnivores, and humans. The recent eradication of rinderpest virus (RPV) and the active campaigns for eradication of the human-speci'c measles virus (MeV) have raised signi'cant concerns that the remaining morbilliviruses may emerge in so-called vacated ecological niches. Seeking to assess the zoonotic potential of nonhuman morbilliviruses within human populations, we found that peste des petits ruminants virus (PPRV)—the small-ruminant morbillivirus—is restricted at the point of entry into human cells due to de'cient interactions with human SLAMF1—the immune cell receptor for morbilliviruses. Using a structure-guided approach, we characterized a single amino acid change, mapping to the receptor-binding domain in the PPRV hemagglutinin (H) protein, which overcomes this restriction. The same mutation allowed escape from some cross-protective, human patient, anti-MeV antibodies, raising concerns that PPRV is a pathogen with zoonotic potential. Analysis of natural variation within human and ovine SLAMF1 also identi'ed polymorphisms that could correlate with disease resistance. Finally, the mechanistic nature of the PPRV restriction was also investigated, identifying charge incompatibility and steric hindrance between PPRV H and human SLAMF1 proteins. Importantly, this research was performed entirely using surrogate virus entry assays, negating the requirement for in situ derivation of a human-tropic PPRV and illustrating alternative strategies for identifying gain-of-function mutations in viral pathogens.