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Peer-reviewedCC BY-NC-ND 4.0Proceedings of the National Academy of Sciences of the United States of America

Virus transmission required for maintenance and host adaptation mirrors neurophysiological differences in rabies-derived peptides

  • Alice Remal1,2
  • Emily S. Acheson2,3
  • Patrick A. Leighton1,2
  • Erin E. Rees1,2,3
  • John Rhodes4
  • Brittany C. V. O’Brien5,6
  • Maegan M. Weltzin5,6
  • Karsten Hueffer7
7 affiliations
  1. 1Département de pathologie et microbiologie, Faculté de médecine vétérinaire, Université de Montréal, Québec J2S 2M2, Canada
  2. 2Groupe de recherche en épidémiologie des zoonoses et santé publique, University of Montréal, Québec J2S 2M2, Canada
  3. 3Modelling Hub Division, Applied Public Health Sciences Directorate, Science and Policy Integration Branch, Public Health Agency of Canada, Québec J2S 2M2, Canada
  4. 4Department of Mathematics and Statistics, University of Alaska Fairbanks, Fairbanks, AK 99775
  5. 5Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK 99775
  6. 6Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK 99775
  7. 7Department of Veterinary Medicine, College of Natural Science and Mathematics, University of Alaska Fairbanks, Fairbanks, AK 99775
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Abstract

Pathogen adaptations to new hosts are central to the disease ecology of cross-species transmission and host switching of viruses. The rabies virus is a model for adaptations to different hosts as it induces behavioral changes that facilitate transmission, while being maintained in distinct species-specific cycles of infection. Here, we demonstrate that the rabies virus requires distinct transmission dynamics in two hosts with different ecologies to establish maintenance, using agent-based modeling, analyses of virus glycoprotein-mediated manipulation of neuroreceptor function, and phylogenetic analysis. Epidemiological models suggest that rabies virus variants adapted to arctic foxes, which sustain rabies virus at very low host densities, require a higher probability of transmission than viruses adapted to raccoons. Using in vitro electrophysiology, we demonstrate that the rabies glycoprotein-derived peptides from arctic fox rabies variants are more potent antagonists of alpha7 nicotinic acetylcholine receptors. These findings suggest a possible functional basis for the behavioral modifications that drive enzootic rabies transmission in the context of host ecology. In addition, a large proportion of residues that may drive rabies virus adaptation to raccoons and arctic foxes are found within this neurotoxin-like region. Furthermore, a residue in the neurotoxin-like region of the mature rabies virus glycoprotein (residue 183) has been associated with pathogenicity, host switching, and disease ecology in previous studies. We propose the hypothesis that rabies virus transmission dynamics adapt to the ecology and physiology of novel hosts through the selection of glycoproteins that elicit specific degrees of behavioral modification and transmission probability.

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Cite

BibTeXRIS
BibTeX
@article{remal2026virus,
  title = {{Virus transmission required for maintenance and host adaptation mirrors neurophysiological differences in rabies-derived peptides}},
  author = {Alice Remal and Emily S. Acheson and Patrick A. Leighton and Erin E. Rees and John Rhodes and Brittany C. V. O’Brien and Maegan M. Weltzin and Karsten Hueffer},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2618744123},
  url = {https://doi.org/10.1073/pnas.2618744123},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Virus transmission required for maintenance and host adaptation mirrors neurophysiological differences in rabies-derived peptides
AU  - Alice Remal
AU  - Emily S. Acheson
AU  - Patrick A. Leighton
AU  - Erin E. Rees
AU  - John Rhodes
AU  - Brittany C. V. O’Brien
AU  - Maegan M. Weltzin
AU  - Karsten Hueffer
PY  - 2026
DA  - 2026/10/22
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2618744123
UR  - https://doi.org/10.1073/pnas.2618744123
AB  - Pathogen adaptations to new hosts are central to the disease ecology of cross-species transmission and host switching of viruses. The rabies virus is a model for adaptations to different hosts as it induces behavioral changes that facilitate transmission, while being maintained in distinct species-specific cycles of infection. Here, we demonstrate that the rabies virus requires distinct transmission dynamics in two hosts with different ecologies to establish maintenance, using agent-based modeling, analyses of virus glycoprotein-mediated manipulation of neuroreceptor function, and phylogenetic analysis. Epidemiological models suggest that rabies virus variants adapted to arctic foxes, which sustain rabies virus at very low host densities, require a higher probability of transmission than viruses adapted to raccoons. Using in vitro electrophysiology, we demonstrate that the rabies glycoprotein-derived peptides from arctic fox rabies variants are more potent antagonists of alpha7 nicotinic acetylcholine receptors. These findings suggest a possible functional basis for the behavioral modifications that drive enzootic rabies transmission in the context of host ecology. In addition, a large proportion of residues that may drive rabies virus adaptation to raccoons and arctic foxes are found within this neurotoxin-like region. Furthermore, a residue in the neurotoxin-like region of the mature rabies virus glycoprotein (residue 183) has been associated with pathogenicity, host switching, and disease ecology in previous studies. We propose the hypothesis that rabies virus transmission dynamics adapt to the ecology and physiology of novel hosts through the selection of glycoproteins that elicit specific degrees of behavioral modification and transmission probability.
SN  - 0027-8424
SN  - 1091-6490
ER  -