Differences in Susceptibility to SARS-CoV-2 Infection Among Transgenic hACE2-Hamster Founder Lines

Authors

Scott A. Gibson, Utah State UniversityFollow
Yanan Liu, Utah State UniversityFollow
Rong Li, Utah State UniversityFollow
Brett L. Hurst, Utah State UniversityFollow
Zhiqiang Fan, Utah State UniversityFollow
Venkatraman Siddharthan, Utah State UniversityFollow
Deanna P. Larson, Utah State UniversityFollow
Ashley Y. Sheesley, Utah State UniversityFollow
Rebekah Stewart, Utah State UniversityFollow
Madelyn Kunzler, Utah State UniversityFollow
Irina A. Polejaeva, Utah State UniversityFollow
Arnaud J. Van Wettere, Utah State UniversityFollow
Stefan Moisyadi, University of HawaiiFollow
John D. Morrey, Utah State UniversityFollow
E. Bart Tarbet, Utah State UniversityFollow
Zhongde Wang, Utah State UniversityFollow

Document Type

Article

Author ORCID Identifier

Brett L. Hurst https://orcid.org/0000-0003-1025-5878

Irina A. Polejaeva https://orcid.org/0000-0002-0858-5889

Arnaud J Van Wettere https://orcid.org/0000-0002-9611-1316

Stefan Moisyadi https://orcid.org/0000-0002-5320-4133

E. Bart Tarbet https://orcid.org/0000-0002-4255-9094

Zhongde Wang https://orcid.org/0000-0003-2441-4729

Journal/Book Title/Conference

Viruses

Volume

16

Issue

10

Publisher

MDPI AG

Publication Date

10-17-2024

Journal Article Version

Version of Record

First Page

1

Last Page

20

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Abstract

Animal models that are susceptible to SARS-CoV-2 infection and develop clinical signs like human COVID-19 are desired to understand viral pathogenesis and develop effective medical countermeasures. The golden Syrian hamster is important for the study of SARS-CoV-2 since hamsters are naturally susceptible to SARS-CoV-2. However, infected hamsters show only limited clinical disease and resolve infection quickly. In this study, we describe development of human angiotensin-converting enzyme 2 (hACE2) transgenic hamsters as a model for COVID-19. During development of the model for SARS-CoV-2, we observed that different hACE2 transgenic hamster founder lines varied in their susceptibility to SARS-CoV-2 lethal infection. The highly susceptible hACE2 founder lines F0F35 and F0M41 rapidly progress to severe infection and death within 6 days post-infection (p.i.). Clinical signs included lethargy, weight loss, dyspnea, and mortality. Lethality was observed in a viral dose-dependent manner with a lethal dose as low as 1 × 10^0.15 CCID₅₀. In addition, virus shedding from highly susceptible lines was detected in oropharyngeal swabs on days 2–5 p.i., and virus titers were observed at 10^5.5−6.5 CCID₅₀ in lung and brain tissue by day 4 p.i.. Histopathology revealed that infected hACE2-hamsters developed rhinitis, tracheitis, broncho-interstitial pneumonia, and encephalitis. Mortality in highly susceptible hACE2-hamsters can be attributed to neurologic disease with contributions from the accompanying respiratory disease. In contrast, virus challenge of animals from less susceptible founder lines, F0M44 and F0M51, resulted in only 0–20% mortality. To demonstrate utility of this SARS-CoV-2 infection model, we determined the protective effect of the TLR3 agonist polyinosinic-polycytidylic acid (Poly (I:C)). Prophylactic treatment with Poly (I:C) significantly improved survival in highly susceptible hACE2-hamsters. In summary, our studies demonstrate that hACE2 transgenic hamsters differ in their susceptibility to SARS-CoV-2 infection, based on the transgenic hamster founder line, and that prophylactic treatment with Poly (I:C) was protective in this COVID-19 model of highly susceptible hACE2-hamsters.

Recommended Citation

Gibson, S.A.; Liu, Y.; Li, R.; Hurst, B.L.; Fan, Z.; Siddharthan, V.; Larson, D.P.; Sheesley, A.Y.; Stewart, R.; Kunzler, M.; et al. Differences in Susceptibility to SARS-CoV-2 Infection Among Transgenic hACE2-Hamster Founder Lines. Viruses 2024, 16, 1625. https://doi.org/10.3390/v16101625