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A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection
Ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lacks the intrinsic ability to bind to the mouse ACE2 receptor, and therefore establishment of SARS-CoV-2 mouse models has been limited to the use of mouse-adapted viruses or genetically modified mice. Interestingly, some of the...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9400483/ https://www.ncbi.nlm.nih.gov/pubmed/35924921 http://dx.doi.org/10.1128/jvi.00758-22 |
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author | Abdelnabi, Rana Foo, Caroline S. Kaptein, Suzanne J. F. Boudewijns, Robbert Vangeel, Laura De Jonghe, Steven Jochmans, Dirk Weynand, Birgit Neyts, Johan |
author_facet | Abdelnabi, Rana Foo, Caroline S. Kaptein, Suzanne J. F. Boudewijns, Robbert Vangeel, Laura De Jonghe, Steven Jochmans, Dirk Weynand, Birgit Neyts, Johan |
author_sort | Abdelnabi, Rana |
collection | PubMed |
description | Ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lacks the intrinsic ability to bind to the mouse ACE2 receptor, and therefore establishment of SARS-CoV-2 mouse models has been limited to the use of mouse-adapted viruses or genetically modified mice. Interestingly, some of the variants of concern, such as the Beta B.1.351 variant, show an improved binding to the mouse receptor and hence better replication in different wild-type (WT) mouse species. Here, we describe the establishment of a SARS-CoV-2 Beta B.1.351 variant infection model in male SCID mice as a tool to assess the antiviral efficacy of potential SARS-CoV-2 small-molecule inhibitors. Intranasal infection of male SCID mice with 10(5) 50% tissue culture infective doses (TCID(50)) of the Beta B.1.351 variant resulted in high viral loads in the lungs and moderate signs of lung pathology on day 3 postinfection. Treatment of infected mice with the antiviral drugs molnupiravir (200 mg/kg, twice a day [BID]) or nirmatrelvir (300 mg/kg, BID) for 3 consecutive days significantly reduced the infectious virus titers in the lungs by 2 and 3.9 log(10) TCID(50)/mg of tissue, respectively, and significantly improved lung pathology. Together, these data demonstrate the validity of this SCID mouse Beta B.1.351 variant infection model as a convenient preclinical model for assessment of potential activity of antivirals against SARS-CoV-2. IMPORTANCE Unlike the ancestral SARS-CoV-2 strain, the Beta (B.1.351) variant of concern has been reported to replicate to some extent in WT mice (C57BL/6 and BALB/c). We demonstrate here that infection of SCID mice with the Beta variant resulted in high viral loads in the lungs on day 3 postinfection. Treatment of infected mice with molnupiravir or nirmatrelvir for 3 consecutive days markedly reduced the infectious virus titers in the lungs and improved lung pathology. The SARS-CoV2 SCID mouse infection model, which is ideally suited for antiviral studies, offers an advantage in comparison to other SARS-CoV2 mouse models, in that there is no need for the use of mouse-adapted virus strains or genetically modified mice. Mouse models also have advantages over hamster models because (i) lower amounts of test drugs are needed, (ii) more animals can be housed in a cage, and (iii) reagents to analyze mouse samples are more readily available than those for hamsters. |
format | Online Article Text |
id | pubmed-9400483 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-94004832022-08-25 A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection Abdelnabi, Rana Foo, Caroline S. Kaptein, Suzanne J. F. Boudewijns, Robbert Vangeel, Laura De Jonghe, Steven Jochmans, Dirk Weynand, Birgit Neyts, Johan J Virol Vaccines and Antiviral Agents Ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lacks the intrinsic ability to bind to the mouse ACE2 receptor, and therefore establishment of SARS-CoV-2 mouse models has been limited to the use of mouse-adapted viruses or genetically modified mice. Interestingly, some of the variants of concern, such as the Beta B.1.351 variant, show an improved binding to the mouse receptor and hence better replication in different wild-type (WT) mouse species. Here, we describe the establishment of a SARS-CoV-2 Beta B.1.351 variant infection model in male SCID mice as a tool to assess the antiviral efficacy of potential SARS-CoV-2 small-molecule inhibitors. Intranasal infection of male SCID mice with 10(5) 50% tissue culture infective doses (TCID(50)) of the Beta B.1.351 variant resulted in high viral loads in the lungs and moderate signs of lung pathology on day 3 postinfection. Treatment of infected mice with the antiviral drugs molnupiravir (200 mg/kg, twice a day [BID]) or nirmatrelvir (300 mg/kg, BID) for 3 consecutive days significantly reduced the infectious virus titers in the lungs by 2 and 3.9 log(10) TCID(50)/mg of tissue, respectively, and significantly improved lung pathology. Together, these data demonstrate the validity of this SCID mouse Beta B.1.351 variant infection model as a convenient preclinical model for assessment of potential activity of antivirals against SARS-CoV-2. IMPORTANCE Unlike the ancestral SARS-CoV-2 strain, the Beta (B.1.351) variant of concern has been reported to replicate to some extent in WT mice (C57BL/6 and BALB/c). We demonstrate here that infection of SCID mice with the Beta variant resulted in high viral loads in the lungs on day 3 postinfection. Treatment of infected mice with molnupiravir or nirmatrelvir for 3 consecutive days markedly reduced the infectious virus titers in the lungs and improved lung pathology. The SARS-CoV2 SCID mouse infection model, which is ideally suited for antiviral studies, offers an advantage in comparison to other SARS-CoV2 mouse models, in that there is no need for the use of mouse-adapted virus strains or genetically modified mice. Mouse models also have advantages over hamster models because (i) lower amounts of test drugs are needed, (ii) more animals can be housed in a cage, and (iii) reagents to analyze mouse samples are more readily available than those for hamsters. American Society for Microbiology 2022-08-04 /pmc/articles/PMC9400483/ /pubmed/35924921 http://dx.doi.org/10.1128/jvi.00758-22 Text en Copyright © 2022 Abdelnabi et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Vaccines and Antiviral Agents Abdelnabi, Rana Foo, Caroline S. Kaptein, Suzanne J. F. Boudewijns, Robbert Vangeel, Laura De Jonghe, Steven Jochmans, Dirk Weynand, Birgit Neyts, Johan A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection |
title | A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection |
title_full | A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection |
title_fullStr | A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection |
title_full_unstemmed | A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection |
title_short | A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection |
title_sort | scid mouse model to evaluate the efficacy of antivirals against sars-cov-2 infection |
topic | Vaccines and Antiviral Agents |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9400483/ https://www.ncbi.nlm.nih.gov/pubmed/35924921 http://dx.doi.org/10.1128/jvi.00758-22 |
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