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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.<\/jats:p>","DOI":"10.1073\/pnas.2618744123","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:59:46Z","timestamp":1792688386000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Virus transmission required for maintenance and host adaptation mirrors neurophysiological differences in rabies-derived peptides"],"prefix":"10.1073","volume":"123","author":[{"given":"Alice","family":"Remal","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de pathologie et microbiologie, Facult\u00e9 de m\u00e9decine v\u00e9t\u00e9rinaire, Universit\u00e9 de Montr\u00e9al","place":["Qu\u00e9bec, Canada"]},{"name":"Groupe de recherche en \u00e9pid\u00e9miologie des zoonoses et sant\u00e9 publique, University of Montr\u00e9al","place":["Qu\u00e9bec, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily S.","family":"Acheson","sequence":"additional","affiliation":[{"name":"Groupe de recherche en \u00e9pid\u00e9miologie des zoonoses et sant\u00e9 publique, University of Montr\u00e9al","place":["Qu\u00e9bec, Canada"]},{"id":[{"id":"https:\/\/ror.org\/023xf2a37","id-type":"ROR","asserted-by":"publisher"}],"name":"Modelling Hub Division, Applied Public Health Sciences Directorate, Science and Policy Integration Branch, Public Health Agency of Canada","place":["Qu\u00e9bec, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick A.","family":"Leighton","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de pathologie et microbiologie, Facult\u00e9 de m\u00e9decine v\u00e9t\u00e9rinaire, Universit\u00e9 de Montr\u00e9al","place":["Qu\u00e9bec, Canada"]},{"name":"Groupe de recherche en \u00e9pid\u00e9miologie des zoonoses et sant\u00e9 publique, University of Montr\u00e9al","place":["Qu\u00e9bec, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin E.","family":"Rees","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de pathologie et microbiologie, Facult\u00e9 de m\u00e9decine v\u00e9t\u00e9rinaire, Universit\u00e9 de Montr\u00e9al","place":["Qu\u00e9bec, Canada"]},{"name":"Groupe de recherche en \u00e9pid\u00e9miologie des zoonoses et sant\u00e9 publique, University of Montr\u00e9al","place":["Qu\u00e9bec, Canada"]},{"id":[{"id":"https:\/\/ror.org\/023xf2a37","id-type":"ROR","asserted-by":"publisher"}],"name":"Modelling Hub Division, Applied Public Health Sciences Directorate, Science and Policy Integration Branch, Public Health Agency of Canada","place":["Qu\u00e9bec, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9921-1091","authenticated-orcid":false,"given":"John","family":"Rhodes","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01j7nq853","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Mathematics and Statistics, University of Alaska Fairbanks","place":["Fairbanks"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany C. 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