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Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential

Abdullah, Nurshariza and Kelly, James T and Graham, Stephen C and Birch, Jamie and Gonçalves-Carneiro, Daniel and Mitchell, Tim and Thompson, Robin N and Lythgoe, Katrina A and Logan, Nicola and Hosie, Margaret J and Bavro, Vassiliy N and Willett, Brian J and Heaton, Michael P and Bailey, Dalan (2018) 'Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential.' Journal of Virology, 92 (23). ISSN 0022-538X

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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-specific measles virus (MeV) have raised significant 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 deficient 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 identified 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. IMPORTANCE A significant proportion of viral pandemics occur following zoonotic transmission events, where animal-associated viruses jump species into human populations. In order to provide forewarnings of 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 levels. In this study, we demonstrated 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, without generation of a fully infectious virus with this phenotype.

Item Type: Article
Subjects: Q Science > QR Microbiology > QR355 Virology
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 22 Nov 2018 16:18
Last Modified: 20 Aug 2019 06:15
URI: http://repository.essex.ac.uk/id/eprint/23519

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