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Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model

A plethora of bat-associated lyssaviruses potentially capable of causing the fatal disease rabies are known today. Transmitted via infectious saliva, occasionally-reported spillover infections from bats to other mammals demonstrate the permeability of the species-barrier and highlight the zoonotic p...

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Autores principales: Klein, Antonia, Eggerbauer, Elisa, Potratz, Madlin, Zaeck, Luca M., Calvelage, Sten, Finke, Stefan, Müller, Thomas, Freuling, Conrad M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8797209/
https://www.ncbi.nlm.nih.gov/pubmed/35041652
http://dx.doi.org/10.1371/journal.pntd.0009845
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author Klein, Antonia
Eggerbauer, Elisa
Potratz, Madlin
Zaeck, Luca M.
Calvelage, Sten
Finke, Stefan
Müller, Thomas
Freuling, Conrad M.
author_facet Klein, Antonia
Eggerbauer, Elisa
Potratz, Madlin
Zaeck, Luca M.
Calvelage, Sten
Finke, Stefan
Müller, Thomas
Freuling, Conrad M.
author_sort Klein, Antonia
collection PubMed
description A plethora of bat-associated lyssaviruses potentially capable of causing the fatal disease rabies are known today. Transmitted via infectious saliva, occasionally-reported spillover infections from bats to other mammals demonstrate the permeability of the species-barrier and highlight the zoonotic potential of bat-related lyssaviruses. However, it is still unknown whether and, if so, to what extent, viruses from different lyssavirus species vary in their pathogenic potential. In order to characterize and systematically compare a broader group of lyssavirus isolates for their viral replication kinetics, pathogenicity, and virus release through saliva-associated virus shedding, we used a mouse infection model comprising a low (10(2) TCID(50)) and a high (10(5) TCID(50)) inoculation dose as well as three different inoculation routes (intramuscular, intranasal, intracranial). Clinical signs, incubation periods, and survival were investigated. Based on the latter two parameters, a novel pathogenicity matrix was introduced to classify lyssavirus isolates. Using a total of 13 isolates from ten different virus species, this pathogenicity index varied within and between virus species. Interestingly, Irkut virus (IRKV) and Bokeloh bat lyssavirus (BBLV) obtained higher pathogenicity scores (1.14 for IRKV and 1.06 for BBLV) compared to rabies virus (RABV) isolates ranging between 0.19 and 0.85. Also, clinical signs differed significantly between RABV and other bat lyssaviruses. Altogether, our findings suggest a high diversity among lyssavirus isolates concerning survival, incubation period, and clinical signs. Virus shedding significantly differed between RABVs and other lyssaviruses. Our results demonstrated that active shedding of infectious virus was exclusively associated with two RABV isolates (92% for RABV-DogA and 67% for RABV-Insectbat), thus providing a potential explanation as to why sustained spillovers are solely attributed to RABVs. Interestingly, 3D imaging of a selected panel of brain samples from bat-associated lyssaviruses demonstrated a significantly increased percentage of infected astrocytes in mice inoculated with IRKV (10.03%; SD±7.39) compared to RABV-Vampbat (2.23%; SD±2.4), and BBLV (0.78%; SD±1.51), while only individual infected cells were identified in mice infected with Duvenhage virus (DUVV). These results corroborate previous studies on RABV that suggest a role of astrocyte infection in the pathogenicity of lyssaviruses.
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spelling pubmed-87972092022-01-29 Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model Klein, Antonia Eggerbauer, Elisa Potratz, Madlin Zaeck, Luca M. Calvelage, Sten Finke, Stefan Müller, Thomas Freuling, Conrad M. PLoS Negl Trop Dis Research Article A plethora of bat-associated lyssaviruses potentially capable of causing the fatal disease rabies are known today. Transmitted via infectious saliva, occasionally-reported spillover infections from bats to other mammals demonstrate the permeability of the species-barrier and highlight the zoonotic potential of bat-related lyssaviruses. However, it is still unknown whether and, if so, to what extent, viruses from different lyssavirus species vary in their pathogenic potential. In order to characterize and systematically compare a broader group of lyssavirus isolates for their viral replication kinetics, pathogenicity, and virus release through saliva-associated virus shedding, we used a mouse infection model comprising a low (10(2) TCID(50)) and a high (10(5) TCID(50)) inoculation dose as well as three different inoculation routes (intramuscular, intranasal, intracranial). Clinical signs, incubation periods, and survival were investigated. Based on the latter two parameters, a novel pathogenicity matrix was introduced to classify lyssavirus isolates. Using a total of 13 isolates from ten different virus species, this pathogenicity index varied within and between virus species. Interestingly, Irkut virus (IRKV) and Bokeloh bat lyssavirus (BBLV) obtained higher pathogenicity scores (1.14 for IRKV and 1.06 for BBLV) compared to rabies virus (RABV) isolates ranging between 0.19 and 0.85. Also, clinical signs differed significantly between RABV and other bat lyssaviruses. Altogether, our findings suggest a high diversity among lyssavirus isolates concerning survival, incubation period, and clinical signs. Virus shedding significantly differed between RABVs and other lyssaviruses. Our results demonstrated that active shedding of infectious virus was exclusively associated with two RABV isolates (92% for RABV-DogA and 67% for RABV-Insectbat), thus providing a potential explanation as to why sustained spillovers are solely attributed to RABVs. Interestingly, 3D imaging of a selected panel of brain samples from bat-associated lyssaviruses demonstrated a significantly increased percentage of infected astrocytes in mice inoculated with IRKV (10.03%; SD±7.39) compared to RABV-Vampbat (2.23%; SD±2.4), and BBLV (0.78%; SD±1.51), while only individual infected cells were identified in mice infected with Duvenhage virus (DUVV). These results corroborate previous studies on RABV that suggest a role of astrocyte infection in the pathogenicity of lyssaviruses. Public Library of Science 2022-01-18 /pmc/articles/PMC8797209/ /pubmed/35041652 http://dx.doi.org/10.1371/journal.pntd.0009845 Text en © 2022 Klein et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Klein, Antonia
Eggerbauer, Elisa
Potratz, Madlin
Zaeck, Luca M.
Calvelage, Sten
Finke, Stefan
Müller, Thomas
Freuling, Conrad M.
Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model
title Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model
title_full Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model
title_fullStr Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model
title_full_unstemmed Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model
title_short Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model
title_sort comparative pathogenesis of different phylogroup i bat lyssaviruses in a standardized mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8797209/
https://www.ncbi.nlm.nih.gov/pubmed/35041652
http://dx.doi.org/10.1371/journal.pntd.0009845
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