Delineating morbillivirus entry, dissemination and airborne transmission by studying in vivo competition of multicolor canine distemper viruses in ferrets
Identification of cellular receptors and characterization of viral tropism in animal models have vastly improved our understanding of morbillivirus pathogenesis. However, specific aspects of viral entry, dissemination and transmission remain difficult to recapitulate in animal models. Here, we used...
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Published in | PLoS pathogens Vol. 13; no. 5; p. e1006371 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
08.05.2017
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | Identification of cellular receptors and characterization of viral tropism in animal models have vastly improved our understanding of morbillivirus pathogenesis. However, specific aspects of viral entry, dissemination and transmission remain difficult to recapitulate in animal models. Here, we used three virologically identical but phenotypically distinct recombinant (r) canine distemper viruses (CDV) expressing different fluorescent reporter proteins for in vivo competition and airborne transmission studies in ferrets (Mustela putorius furo). Six donor ferrets simultaneously received three rCDVs expressing green, red or blue fluorescent proteins via conjunctival (ocular, Oc), intra-nasal (IN) or intra-tracheal (IT) inoculation. Two days post-inoculation sentinel ferrets were placed in physically separated adjacent cages to assess airborne transmission. All donor ferrets developed lymphopenia, fever and lethargy, showed progressively increasing systemic viral loads and were euthanized 14 to 16 days post-inoculation. Systemic replication of virus inoculated via the Oc, IN and IT routes was detected in 2/6, 5/6 and 6/6 ferrets, respectively. In five donor ferrets the IT delivered virus dominated, although replication of two or three different viruses was detected in 5/6 animals. Single lymphocytes expressing multiple fluorescent proteins were abundant in peripheral blood and lymphoid tissues, demonstrating the occurrence of double and triple virus infections. Transmission occurred efficiently and all recipient ferrets showed evidence of infection between 18 and 22 days post-inoculation of the donor ferrets. In all cases, airborne transmission resulted in replication of a single-colored virus, which was the dominant virus in the donor ferret. This study demonstrates that morbilliviruses can use multiple entry routes in parallel, and co-infection of cells during viral dissemination in the host is common. Airborne transmission was efficient, although transmission of viruses expressing a single color suggested a bottleneck event. The identity of the transmitted virus was not determined by the site of inoculation but by the viral dominance during dissemination. |
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Bibliography: | new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Viroclinics Biosciences, Rotterdam, The Netherlands Current address: ProQR Therapeutics, Leiden, The Netherlands Conceptualization: RDdV ML LJR ADMEO RLdS WPD.Formal analysis: RDdV RLdS.Funding acquisition: RAMF ADMEO RLdS WPD.Investigation: RDdV ML AdJ LJR RJV GvA DvR PRWAvR RLdS WPD.Methodology: SH TK RAMF WPD.Project administration: RDdV RLdS WPD.Resources: SH TK RAMF ADMEO.Supervision: TK RAMF ADMEO RLdS WPD.Visualization: RDdV.Writing – original draft: RDdV.Writing – review & editing: RDdV ML LJR DvR SH TK RAMF ADMEO RLdS WPD. ADME Osterhaus wishes to declare, for the avoidance of any misunderstanding on competing interests, that he co-founded and is chief scientific officer of Viroclinics Biosciences (www.viroclinics.eu). G. van Amerongen is currently employed by Viroclinics Biosciences, and RJ Verburgh is currently employed by ProQR Therapeutics. However, for clarification, no materials or support were received from these companies, and no agreements were in place concerning the execution or publication of this work. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials. The other authors have declared that no competing interests exist. Current address: Research Centre for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany |
ISSN: | 1553-7374 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1006371 |